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    Clinical Trial Results:
    A Phase IIb, 2-Arm, Randomized, Double-blind, Placebo-Controlled, Multicentre Study to Optimize Diamyd® Therapy Administered into Lymph Nodes Combined with Oral Vitamin D to Investigate the Impact on the Progression of Type 1 diabetes

    Summary
    EudraCT number
    		 2017-001861-25
    Trial protocol
    		 SE   CZ   ES   NL  
    Global end of trial date
    27 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Oct 2021
    First version publication date
    13 Oct 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DIAGNODE-2 (D/P2/17/6)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03345004
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Diamyd Medical AB
    Sponsor organisation address
    Kungsgatan 29, Stockholm, Sweden, SE-111 56
    Public contact
    Clinical Study Director, Diamyd Medical AB, clinicaltrials@diamyd.com
    Scientific contact
    Clinical Study Director, Diamyd Medical AB, clinicaltrials@diamyd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000609-PIP01-09
    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
    27 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of Diamyd, administered into lymph nodes in combination with an oral vitamin D regimen, compared to placebo in terms of preserving endogenous insulin secretion as measured by C-peptide.
    Protection of trial subjects
    The final study protocol, including any substantial amendments and the final version of the subject information and consent form, were reviewed and approved by an Independent Ethics Committee and Competent Authorities prior to inclusion of subjects. The study was conducted in compliance with the protocol, regulatory requirements, good clinical practice (GCP) and the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the World Medical Association. The investigator was responsible for giving the patients and his/her parents/caregivers full and adequate verbal and written information about the nature, purpose, possible risk and benefit of the study. Patients and, if applicable, his/her parents/caregivers were also notified that they were free to withdraw from the study at any time. The patients and parents/caregivers had reasonable time to read and understand the information before signing. The investigator was responsible for obtaining signed informed consent from all patients before including the patient in any study related procedures.
    Background therapy
    		 Standard of care
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2017
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 43
    Country: Number of subjects enrolled
    Sweden: 31
    Country: Number of subjects enrolled
    Czech Republic: 33
    Worldwide total number of subjects
    109
    EEA total number of subjects
    109
    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)
    75
    Adults (18-64 years)
    34
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited at 18 sites in total, in Spain, Sweden, Czech Republic and the Netherlands. Patients were recruited from 07 December 2017 and the last patient's last visit was on 24 April 2021.

    Pre-assignment
    Screening details
    		 Inclusion: Patients aged 12-24 with type-1 diabetes diagnosed for at least 6 months with fasting C-peptide over 0.12 nmol/L and positive for GAD65A (<50,000 IU/mL) with adequate contraception. Exclusion: patients using immunosuppressants, anti-inflammatory drugs, anti-diabetics (other than insulin), vitamin D, with history of anaemia or epilepsy.

    Period 1
    Period 1 title
    Main Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Diamyd + vitamin D (FAS, Main Study)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd® intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    4 ug administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Vitamin D
    Investigational medicinal product code
    Other name
    D-vitaminolja ACO orala droppar, lösning, 80 IE/droppe
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    2000 IU/day (25 drops á 80 IE/drop) from Day 1 to Day 120.

    Arm title
    		 Placebo (FAS, Main Study)
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Placebo oral drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Administered daily from Day 1 to Day 120.

    Arm title
    		 Diamyd + vitamin D (HLA DR3-DQ2, Main Study)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd® intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    4 ug administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Vitamin D
    Investigational medicinal product code
    Other name
    D-vitaminolja ACO orala droppar, lösning, 80 IE/droppe
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    2000 IU/day (25 drops á 80 IE/drop) from Day 1 to Day 120.

    Arm title
    		 Placebo (HLA DR3-DQ2, Main Study)
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Placebo oral drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Administered daily from Day 1 to Day 120.

    Number of subjects in period 1
    		Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study)
    Started
    57
    52
    29
    19
    Completed
    56
    51
    28
    18
    Not completed
    1
    1
    1
    1
         Physician decision
    1
    -
    1
    -
         Consent withdrawn by subject
    -
    1
    -
    1
    Period 2
    Period 2 title
    Extension Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Diamyd + vitamin D (Extension)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd® intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    4 ug administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Vitamin D
    Investigational medicinal product code
    Other name
    D-vitaminolja ACO orala droppar, lösning, 80 IE/droppe
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    2000 IU/day (25 drops á 80 IE/drop) from Day 1 to Day 120.

    Arm title
    		 Placebo (Extension)
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Placebo oral drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Administered daily from Day 1 to Day 120.

    Arm title
    		 Diamyd + vitamin D (HLA DR3-DQ2, Extension)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diamyd® intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    4 ug administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Vitamin D
    Investigational medicinal product code
    Other name
    D-vitaminolja ACO orala droppar, lösning, 80 IE/droppe
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    2000 IU/day (25 drops á 80 IE/drop) from Day 1 to Day 120.

    Arm title
    		 Placebo (HLA DR3-DQ2, Extension)
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo intralymphatic injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Administered in the inguinal lymph node on Day 30, 60 and 90.

    Investigational medicinal product name
    Placebo oral drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Administered daily from Day 1 to Day 120.

    Number of subjects in period 2
    		Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Started
    30
    23
    15
    8
    Completed
    28
    22
    15
    8
    Not completed
    2
    1
    0
    0
         Lost to follow-up
    2
    1
    -
    -

    Baseline characteristics

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

    Reporting group values
    		 Main Study Total
    Number of subjects
    		 109 109
    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)
    		 75 75
        Adults (18-64 years)
    		 34 34
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.4 ± 4.1 -
    Gender categorical
    Units: Subjects
        Female
    		 47 47
        Male
    		 62 62

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Diamyd + vitamin D (FAS, Main Study)
    Reporting group description
    		 -

    Reporting group title
    Placebo (FAS, Main Study)
    Reporting group description
    		 -

    Reporting group title
    Diamyd + vitamin D (HLA DR3-DQ2, Main Study)
    Reporting group description
    		 -

    Reporting group title
    Placebo (HLA DR3-DQ2, Main Study)
    Reporting group description
    		 -
    Reporting group title
    Diamyd + vitamin D (Extension)
    Reporting group description
    		 -

    Reporting group title
    Placebo (Extension)
    Reporting group description
    		 -

    Reporting group title
    Diamyd + vitamin D (HLA DR3-DQ2, Extension)
    Reporting group description
    		 -

    Reporting group title
    Placebo (HLA DR3-DQ2, Extension)
    Reporting group description
    		 -

    Primary: Change in C-peptide area under the curve (AUC)

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    End point title
    		 Change in C-peptide area under the curve (AUC)
    End point description
    Data is unitless as it is back-transformed from log scale.
    End point type
    Primary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    55
    48
    29
    17
    28
    22
    15
    8
    Units: unitless
        arithmetic mean (standard deviation)
    0.551 ± 1.715
    0.506 ± 2.163
    0.663 ± 1.511
    0.425 ± 2.436
    0.376 ± 1.738
    0.453 ± 1.914
    0.449 ± 1.642
    0.381 ± 1.706
    Statistical analysis title
    		 MMRM of change in C-peptide AUC
    Comparison groups
    Diamyd + vitamin D (FAS, Main Study) v Placebo (FAS, Main Study)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5009
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated ratio
    Point estimate
    1.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.845
         upper limit
    		 1.408
    Statistical analysis title
    		 MMRM of change in C-peptide AUC: HLA DR3-DQ2
    Comparison groups
    Diamyd + vitamin D (HLA DR3-DQ2, Main Study) v Placebo (HLA DR3-DQ2, Main Study)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0078
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated ratio
    Point estimate
    1.557
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.126
         upper limit
    		 2.153
    Statistical analysis title
    		 MMRM of change in C-peptide AUC: Extension
    Comparison groups
    Diamyd + vitamin D (Extension) v Placebo (Extension)
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2215
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated ratio
    Point estimate
    0.807
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.569
         upper limit
    		 1.143
    Statistical analysis title
    		 MMRM of change in C-peptide AUC: Extension DR3-DQ2
    Comparison groups
    Diamyd + vitamin D (HLA DR3-DQ2, Extension) v Placebo (HLA DR3-DQ2, Extension)
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4038
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated ratio
    Point estimate
    1.197
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.781
         upper limit
    		 1.834

    Secondary: Change in Insulin-dose-adjusted HbA1c (IDAA1c)

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    End point title
    		 Change in Insulin-dose-adjusted HbA1c (IDAA1c)
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    51
    44
    28
    15
    23
    22
    13
    8
    Units: unitless
        arithmetic mean (standard deviation)
    0.757 ± 1.851
    0.377 ± 2.183
    0.663 ± 1.627
    0.667 ± 2.788
    1.327 ± 2.187
    1.195 ± 1.881
    1.402 ± 1.619
    0.803 ± 2.481
    No statistical analyses for this end point

    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 between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    56
    51
    29
    18
    28
    22
    15
    8
    Units: mmol/mol haemoglobin
        arithmetic mean (standard deviation)
    1.04 ± 15.87
    0.53 ± 14.57
    0.87 ± 14.34
    -0.98 ± 18.75
    3.94 ± 13.51
    4.29 ± 14.40
    6.00 ± 11.60
    1.36 ± 21.07
    No statistical analyses for this end point

    Secondary: Change in daily exogenous insulin consumption

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    End point title
    		 Change in daily exogenous insulin consumption
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    51
    44
    28
    15
    23
    22
    13
    8
    Units: IU/kg/24h
        arithmetic mean (standard deviation)
    0.183 ± 0.285
    0.094 ± 0.342
    0.143 ± 0.196
    0.153 ± 0.399
    0.256 ± 0.342
    0.201 ± 0.275
    0.233 ± 0.317
    0.173 ± 0.247
    No statistical analyses for this end point

    Secondary: Change in glycaemic variability

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    End point title
    		 Change in glycaemic variability
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    49
    39
    25
    12
    20
    16
    13
    6
    Units: per day
    arithmetic mean (standard deviation)
        70-180 mg/dL (hours)
    -2.479 ± 4.638
    -2.451 ± 4.012
    -1.724 ± 3.346
    -3.920 ± 4.090
    -3.104 ± 2.859
    -2.598 ± 4.295
    -2.643 ± 3.305
    -4.270 ± 4.420
        50-70 mg/dL (hours)
    -0.035 ± 2.416
    0.197 ± 1.961
    0.034 ± 2.992
    0.581 ± 1.057
    -0.041 ± 2.142
    -0.185 ± 2.150
    -0.325 ± 2.529
    0.159 ± 1.697
        <50 mg/dL (minutes)
    15.7 ± 46.4
    9.0 ± 88.4
    16.7 ± 59.3
    48.1 ± 107.0
    13.6 ± 47.2
    18.6 ± 97.0
    11.2 ± 56.0
    46.7 ± 72.7
    No statistical analyses for this end point

    Secondary: Proportion of patients with IDAA1c ≤ 9

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    End point title
    		 Proportion of patients with IDAA1c ≤ 9
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of patients at Month 15 (Main Study reporting groups) and at Month 24 (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    51
    44
    28
    15
    23
    22
    13
    8
    Units: percent
        number (confidence interval 95%)
    62.7 (48.1 to 75.9)
    61.4 (45.5 to 75.6)
    78.6 (59.0 to 91.7)
    40.0 (16.3 to 67.7)
    60.9 (38.5 to 80.3)
    54.5 (32.2 to 75.6)
    69.2 (38.6 to 90.9)
    62.5 (24.5 to 91.5)
    No statistical analyses for this end point

    Secondary: Proportion of patients with stimulated maximum C-peptide above 0.2 nmol/L

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    End point title
    		 Proportion of patients with stimulated maximum C-peptide above 0.2 nmol/L
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of patients at Month 15 (Main Study reporting groups) and at Month 24 (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    55
    49
    29
    17
    28
    22
    15
    8
    Units: percent
        number (confidence interval 95%)
    92.7 (82.4 to 98.0)
    75.5 (61.1 to 86.7)
    96.6 (82.2 to 99.9)
    70.6 (44.0 to 89.7)
    75.0 (55.1 to 89.3)
    72.7 (49.8 to 89.3)
    80.0 (51.9 to 95.7)
    62.5 (24.5 to 91.5)
    No statistical analyses for this end point

    Secondary: Proportion of patients with stimulated 90-minute C-peptide above 0.2 nmol/L

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    End point title
    		 Proportion of patients with stimulated 90-minute C-peptide above 0.2 nmol/L
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of patients at Month 15 (Main Study reporting groups) and at Month 24 (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    55
    49
    29
    17
    27
    22
    14
    8
    Units: percent
        number (confidence interval 95%)
    87.3 (75.5 to 94.7)
    71.4 (56.7 to 83.4)
    96.6 (82.2 to 99.9)
    64.7 (38.3 to 85.8)
    70.4 (49.8 to 86.2)
    68.2 (45.1 to 86.1)
    71.4 (41.9 to 91.6)
    62.5 (24.5 to 91.5)
    No statistical analyses for this end point

    Secondary: Number of self-reported episodes of severe hypoglycaemia

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    End point title
    		 Number of self-reported episodes of severe hypoglycaemia
    End point description
    End point type
    Secondary
    End point timeframe
    Between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    57
    52
    29
    19
    30
    23
    15
    8
    Units: episodes
    0
    6
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with at least 1 severe hypoglycaemic event

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    End point title
    		 Number of patients with at least 1 severe hypoglycaemic event
    End point description
    End point type
    Secondary
    End point timeframe
    Between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    57
    52
    29
    19
    30
    23
    15
    8
    Units: patients
    0
    1
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    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
    End point type
    Secondary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    55
    49
    29
    17
    28
    22
    15
    8
    Units: nmol/L
        arithmetic mean (standard deviation)
    -0.350 ± 0.463
    -0.300 ± 0.350
    -0.257 ± 0.400
    -0.277 ± 0.349
    -0.546 ± 0.295
    -0.403 ± 0.306
    -0.557 ± 0.319
    -0.520 ± 0.364
    No statistical analyses for this end point

    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
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension) Diamyd + vitamin D (HLA DR3-DQ2, Extension) Placebo (HLA DR3-DQ2, Extension)
    Number of subjects analysed
    55
    49
    29
    17
    28
    22
    15
    8
    Units: nmol/L
        arithmetic mean (standard deviation)
    -0.115 ± 0.148
    -0.106 ± 0.169
    -0.081 ± 0.100
    -0.095 ± 0.190
    -0.144 ± 0.160
    -0.139 ± 0.122
    -0.082 ± 0.119
    -0.150 ± 0.107
    No statistical analyses for this end point

    Secondary: C-peptide measured at 30, 60, 90 and 120 minutes during MMTT

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    End point title
    		 C-peptide measured at 30, 60, 90 and 120 minutes during MMTT
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 15.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (HLA DR3-DQ2, Main Study) Placebo (HLA DR3-DQ2, Main Study)
    Number of subjects analysed
    55
    49
    29
    19
    Units: nmol/L
    arithmetic mean (standard deviation)
        30 min
    0.376 ± 0.295
    0.374 ± 0.330
    0.659 ± 0.352
    0.580 ± 0.282
        60 min
    0.536 ± 0.383
    0.495 ± 0.411
    0.911 ± 0.393
    0.715 ± 0.308
        90 min
    0.645 ± 0.495
    0.562 ± 0.438
    1.016 ± 0.451
    0.717 ± 0.318
        120 min
    0.691 ± 0.542
    0.590 ± 0.444
    1.065 ± 0.430
    0.728 ± 0.317
    No statistical analyses for this end point

    Secondary: Change in body weight and BMI

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    End point title
    		 Change in body weight and BMI [1]
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups) or between baseline and 24 months (Extension Study reporting groups).
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension)
    Number of subjects analysed
    56
    51
    28
    22
    Units: unit(s)
    arithmetic mean (standard deviation)
        Body weight (kg)
    4.3 ± 5.0
    5.6 ± 5.4
    6.5 ± 6.9
    6.8 ± 6.8
        Body mass index (kg/m2)
    0.8 ± 1.4
    1.3 ± 1.6
    1.2 ± 1.9
    1.9 ± 2.0
    No statistical analyses for this end point

    Secondary: Injection site reactions

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    End point title
    		 Injection site reactions [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 15 months (Main Study reporting groups)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study)
    Number of subjects analysed
    57
    52
    Units: severe injection site reactions
    10
    3
    No statistical analyses for this end point

    Secondary: Laboratory assessments

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    End point title
    		 Laboratory assessments [3]
    End point description
    Clinically significant abnormal results from laboratory measurements (haematology and clinical chemistry) and urinalysis.
    End point type
    Secondary
    End point timeframe
    From Screening until 15 months (Main Study reporting groups) or from Screening until 24 months (Extension Study reporting groups)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension)
    Number of subjects analysed
    57
    52
    30
    23
    Units: clinically significant abnormal results
    11
    3
    3
    3
    No statistical analyses for this end point

    Secondary: Physical and neurological examination

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    End point title
    		 Physical and neurological examination [4]
    End point description
    End point type
    Secondary
    End point timeframe
    From Screening until 15 months (Main Study reporting groups) or from Screening until 24 months (Extension Study reporting groups)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension)
    Number of subjects analysed
    57
    52
    30
    23
    Units: clinically significant abnormal results
        Physical examination
    15
    9
    10
    1
        Neurological examination
    4
    0
    4
    0
    No statistical analyses for this end point

    Secondary: GAD65A titer

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    End point title
    		 GAD65A titer [5]
    End point description
    Last assessment corresponds to Month 15 for the Main Study reporting groups and Month 24 for the Extension Study reporting groups
    End point type
    Secondary
    End point timeframe
    At baseline and 15 months (Main Study reporting groups) or at Baseline and 24 months (Extension Study reporting groups)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension)
    Number of subjects analysed
    57
    52
    30
    23
    Units: IU/mL
    arithmetic mean (standard deviation)
        Baseline
    731.3 ± 2302.9
    627.3 ± 1829.9
    677.8 ± 2060.8
    168.0 ± 283.5
        Last assessment
    19941.2 ± 23083.6
    19197.7 ± 22218.7
    18972.5 ± 21432.4
    18253.7 ± 21199.0
    No statistical analyses for this end point

    Secondary: Vital signs (blood pressure)

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    End point title
    		 Vital signs (blood pressure) [6]
    End point description
    End point type
    Secondary
    End point timeframe
    From Screening until 15 months (Main Study reporting groups) or from Screening until 24 months (Extension Study reporting groups)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension)
    Number of subjects analysed
    57
    52
    30
    23
    Units: clinically significant abnormal results
        Systolic blood pressure
    0
    0
    0
    0
        Diastolic blood pressure
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Quality of life: EQ-5D-5L

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    End point title
    		 Quality of life: EQ-5D-5L [7]
    End point description
    Last assessment corresponds to Month 15 for the Main Study reporting groups and Month 24 for the Extension Study reporting groups
    End point type
    Secondary
    End point timeframe
    At baseline and 15 months (Main Study reporting groups) or at Baseline and 24 months (Extension Study reporting groups)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was summarised overall only, not further split by HLA subgroup.
    End point values
    		 Diamyd + vitamin D (FAS, Main Study) Placebo (FAS, Main Study) Diamyd + vitamin D (Extension) Placebo (Extension)
    Number of subjects analysed
    48
    47
    26
    21
    Units: unitless
    median (inter-quartile range (Q1-Q3))
        Baseline
    1.000 (0.922 to 1.000)
    1.000 (0.919 to 1.000)
    1.000 (0.922 to 1.000)
    1.000 (0.919 to 1.000)
        Last assessment
    1.000 (0.919 to 1.000)
    1.000 (1.000 to 1.000)
    1.000 (0.919 to 1.000)
    1.000 (0.919 to 1.000)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events, from start of Diamyd/Placebo treatment until Month 24.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Diamyd + vitamin D
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Diamyd + vitamin D Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 52 (5.77%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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 + vitamin D Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 57 (31.58%)
    12 / 52 (23.08%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 52 (3.85%)
         occurrences all number
    4
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 57 (17.54%)
    10 / 52 (19.23%)
         occurrences all number
    13
    17
    Viral infection
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 52 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2017
    Amendment 1 included: • Addition of new inclusion criterion • Clarification on all visits timing • Specification of c-peptid concentration at screening visit • Clarification on the physical examination outcome • Clarification on the lymph node injection side • Clarification on the relationship to study medication
    21 Aug 2017
    Amendment 4 included: • Patients taking Vitamin D before screening had to stop it during trial (new exclusion criterion)
    28 Jun 2018
    Amendment 5 included: • Addition of 2 sites in The Netherlands (new country) • Increase the number of total patients 106 instead of 80 • Increase the recruitment period in 4 months (16 in total) • ICFs were updated
    18 Jun 2019
    Amendment 6 included: • All patients that were ongoing, were asked to participate in the Extension Study Period which included Visit 8 at month 24. • Exploratory endpoints included all data collected at the 24-month follow-up visit • ICFs were updated for the patients that approved to participate in the Extension Study
    15 May 2020
    Amendment 7 included: • Addition of key secondary endpoints to evaluate diabetic status • Correction of secondary endpoints and addition of new ones (body weight, body mass index and serological test for Covid-19) • Upgrade of analysis sets for statistical analysis • Upgrade of primary endpoint variable analysis; secondary efficacy endpoint variables analysis; secondary variables of diabetic status analysis; and exploratory endpoints variables analysis

    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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