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    Clinical Trial Results:
    DIAPREV-IT Diabetes Prevention Immune Tolerance. A double-blind, randomized investigator-initiated study to determine the safety and the effect of Diamyd® on the progression to type 1 diabetes in children with multiple islet cell autoantibodies.

    Summary
    EudraCT number
    		 2008-007484-16
    Trial protocol
    		 SE  
    Global end of trial date
    31 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2020
    First version publication date
    09 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DIAPREV/2008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01122446
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Skåne University Hospital
    Sponsor organisation address
    Jan Waldenströms gata 35, hus 60, Malmö, Sweden,
    Public contact
    Helena Elding Larsson, Skåne University Hospital, 46 040-337676, helena.larsson@med.lu.se
    Scientific contact
    Helena Elding Larsson, Skåne University Hospital, 46 040-337676, helena.larsson@med.lu.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
    22 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that Diamyd® is safe in children at risk for type 1 diabetes from 4 years of age. The subjects will be followed for 5 years.
    Protection of trial subjects
    After the injection of Diamyd/placebo at visits 1 and 2, each trial participant was to remain at the study clinic for at least 1h and monitored by the study personnel. Additionally, the participants were offered to stay at the clinic for an additional 2h or contact the investigator by phone.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2009
    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: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    48
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 55 children were screened for participation. Of those, 4 did not fulfil the inclusion criteria of positive autoantibodies to GAD65 (GADA) and at least one more islet autoantibody, or had already developed diabetes at screening. For one child, the parents changed their mind about participation and withdrew the child before the first treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Diamyd
    Arm description
    		 ALUM-rhGAD65
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd
    Investigational medicinal product code
    Other name
    ALUM-rhGAD65
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 subcutaneous injections of 20 microgram each

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 injections

    Number of subjects in period 1
    		Diamyd Placebo
    Started
    25
    25
    Completed
    25
    25
    Period 2
    Period 2 title
    Treatment follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Diamyd
    Arm description
    		 ALUM-rhGAD65
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd
    Investigational medicinal product code
    Other name
    ALUM-rhGAD65
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 subcutaneous injections of 20 microgram each

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 subcutaneous injections

    Number of subjects in period 2
    		Diamyd Placebo
    Started
    25
    25
    Completed
    25
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Diamyd
    Reporting group description
    		 ALUM-rhGAD65

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Diamyd Placebo Total
    Number of subjects
    		 25 25 50
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 6.0 (4.1 to 15.1) 5.0 (4.0 to 17.9) -
    Gender categorical
    Units: Subjects
        Female
    		 11 12 23
        Male
    		 14 13 27
    Population source
    Units: Subjects
        General population
    		 16 18 34
        First degree relative
    		 9 7 16
    Stratum
    Units: Subjects
        2 positive antibodies
    		 7 7 14
        3-6 positive antibodies
    		 18 18 36
    GADA
    Units: Subjects
        Positive
    		 25 25 50
        Negative
    		 0 0 0
    Glucose tolerance
    Units: Subjects
        Impaired
    		 13 13 26
        Normal
    		 12 12 24
    OGTT fasting C-peptide
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 0.21 ± 0.1 0.18 ± 0.09 -
    OGTT 2 hour C-peptide
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 1.22 ± 0.46 1.09 ± 0.6 -
    OGTT AUC C-peptide
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 146.98 ± 62.12 134.82 ± 55.36 -
    OGTT fasting glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.74 ± 0.49 4.67 ± 0.56 -
    OGTT 2 hour glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 6.88 ± 1.61 6.82 ± 2.12 -
    OGTT AUC glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 938.72 ± 190.87 989.63 ± 207.07 -
    HbA1c
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 32.76 ± 3.13 33.84 ± 3.52 -

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Diamyd
    Reporting group description
    		 ALUM-rhGAD65

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Frequency of type 1 diabetes

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    End point title
    		 Frequency of type 1 diabetes
    End point description
    End point type
    Primary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    25
    25
    Units: Days
    8
    10
    Statistical analysis title
    		 Progression to type 1 diabetes
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.574 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.94
    Notes
    [1] - Difference between treatment in time to type 1 diabetes

    Secondary: Change from baseline in FPIR (First-phase Insulin Response)

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    End point title
    		 Change from baseline in FPIR (First-phase Insulin Response)
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    15
    15
    Units: Unknown
        arithmetic mean (standard deviation)
    89.60 ± 63.60
    97.60 ± 63.15
    Statistical analysis title
    		 Change from baseline in FPIR
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - Difference between the treatment groups

    Secondary: Change from baseline in fasting C-peptide

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    End point title
    		 Change from baseline in fasting C-peptide
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    16
    15
    Units: Unknown
        arithmetic mean (standard deviation)
    0.45 ± 0.16
    0.48 ± 0.25
    Statistical analysis title
    		 Change from baseline in fasting C-peptide
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.366
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change from baseline in 120-minutes C-peptide

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    End point title
    		 Change from baseline in 120-minutes C-peptide
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    16
    15
    Units: Unknown
        arithmetic mean (standard deviation)
    1.45 ± 0.5
    1.58 ± 0.7
    Statistical analysis title
    		 Change from baseline in 120-minutes C-peptide
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.384 [3]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - Difference between the treatments

    Secondary: Change from baseline in AUC C-peptide

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    End point title
    		 Change from baseline in AUC C-peptide
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    16
    15
    Units: Unknown
        arithmetic mean (standard deviation)
    184.14 ± 65.59
    183.23 ± 64.78
    Statistical analysis title
    		 Change from baseline in AUC C-peptide
    Comparison groups
    Placebo v Diamyd
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.308 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [4] - Difference between the treatments

    Secondary: Change from baseline in fasting glucose

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    End point title
    		 Change from baseline in fasting glucose
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    17
    15
    Units: Unknown
        arithmetic mean (standard deviation)
    5.36 ± 0.39
    5.29 ± 0.5
    Statistical analysis title
    		 Change from baseline in fasting glucose
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5 [5]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - Difference between treatments

    Secondary: Change from baseline in 120-minutes glucose

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    End point title
    		 Change from baseline in 120-minutes glucose
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    17
    15
    Units: Unknown
        arithmetic mean (standard deviation)
    7.04 ± 3.11
    6.67 ± 2.38
    Statistical analysis title
    		 Change from baseline in AUC glucose
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.565 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - Difference between the treatments

    Secondary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Diamyd Placebo
    Number of subjects analysed
    16
    16
    Units: Unknown
        arithmetic mean (standard deviation)
    34.00 ± 3.12
    34.56 ± 4.23
    Statistical analysis title
    		 Change from baseline in HbA1c
    Comparison groups
    Diamyd v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.151
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to 5 year follow-up or diagnosis of type 1 diabetes.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Diamyd
    Reporting group description
    		 ALUM-rhGAD65

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Diamyd Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Diamyd Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 25 (100.00%)
    25 / 25 (100.00%)
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 25 (12.00%)
         occurrences all number
    3
    3
    Vaccination complication
         subjects affected / exposed
    1 / 25 (4.00%)
    5 / 25 (20.00%)
         occurrences all number
    1
    5
    Fall
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 25 (28.00%)
    6 / 25 (24.00%)
         occurrences all number
    54
    17
    Dizziness
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    2
    Migraine
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    4
    Injection site reaction
         subjects affected / exposed
    24 / 25 (96.00%)
    23 / 25 (92.00%)
         occurrences all number
    43
    43
    Malaise
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    10 / 25 (40.00%)
    19 / 25 (76.00%)
         occurrences all number
    29
    43
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    Seasonal allergy
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 25 (8.00%)
         occurrences all number
    6
    2
    Coeliac disease
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    6 / 25 (24.00%)
    5 / 25 (20.00%)
         occurrences all number
    10
    11
    Diarrhoea
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    4 / 25 (16.00%)
    5 / 25 (20.00%)
         occurrences all number
    5
    7
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 25 (16.00%)
         occurrences all number
    25
    18
    Cough
         subjects affected / exposed
    6 / 25 (24.00%)
    5 / 25 (20.00%)
         occurrences all number
    16
    12
    Oropharyngeal pain
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 25 (12.00%)
         occurrences all number
    5
    5
    Musculoskeletal and connective tissue disorders
    Growing pains
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    7
    Infections and infestations
    Ear infection
         subjects affected / exposed
    3 / 25 (12.00%)
    6 / 25 (24.00%)
         occurrences all number
    5
    11
    Enterobiasis
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 25 (8.00%)
         occurrences all number
    8
    4
    Gastroenteritis
         subjects affected / exposed
    19 / 25 (76.00%)
    17 / 25 (68.00%)
         occurrences all number
    41
    29
    Influenza
         subjects affected / exposed
    7 / 25 (28.00%)
    4 / 25 (16.00%)
         occurrences all number
    9
    4
    Nasopharyngitis
         subjects affected / exposed
    21 / 25 (84.00%)
    21 / 25 (84.00%)
         occurrences all number
    117
    92
    Otitis media
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    3
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Scarlet fever
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Tonsillitis
         subjects affected / exposed
    2 / 25 (8.00%)
    7 / 25 (28.00%)
         occurrences all number
    2
    10
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 25 (52.00%)
    9 / 25 (36.00%)
         occurrences all number
    19
    11
    Varicella
         subjects affected / exposed
    6 / 25 (24.00%)
    6 / 25 (24.00%)
         occurrences all number
    6
    6
    Viral infection
         subjects affected / exposed
    7 / 25 (28.00%)
    2 / 25 (8.00%)
         occurrences all number
    13
    3
    Conjunctivitis
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    4
    Otitis externa
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/2346994
    http://www.ncbi.nlm.nih.gov/pubmed/25381193
    http://www.ncbi.nlm.nih.gov/pubmed/29171140
    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
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