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    Clinical Trial Results:
    Pre-POINT (Primary Oral INsulin Trial) study A dose finding safety and immune efficacy study for primary mucosal insulin therapy in islet autoantibody negative children at high genetic risk for type 1 diabetes

    Summary
    EudraCT number
    		 2005-001621-29
    Trial protocol
    		 DE   AT   GB  
    Global end of trial date
    15 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2024
    First version publication date
    03 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    80804002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Technische Universität Dresden
    Sponsor organisation address
    Helmholtzstraße 10, Dresden, Germany, 01069
    Public contact
    Koordinierungszentrum für Klinische Studien, Medizinische Fakultät C. G. Carus, kontakt@kksdresden.de
    Scientific contact
    Koordinierungszentrum für Klinische Studien, Medizinische Fakultät C. G. Carus, kontakt@kksdresden.de
    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
    15 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to determine the feasibility, safety and bioavailability of oral insulin administration in children with high genetic risk for type 1 diabetes (T1DM) in a dose escalation primary intervention pilot study. To find a dose with proven drug bioavailability to the immune system for use in a phase II/III primary T1DM vaccination trial (POINT study) in genetically at risk subjects.
    Protection of trial subjects
    Only subjects who met all of the study's inclusion criteria and none of the exclusion criteria were enrolled in the study. The occurrence of adverse events was closely monitored.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 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
    United Kingdom: 1
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    25
    EEA total number of subjects
    19
    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)
    25
    Adolescents (12-17 years)
    0
    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
    		 All subjects were screened for eligibility prior to enrollment in the clinical trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Insulin
    Arm description
    		 The study randomized in study blocks of 5 participants. Children randomized in the first block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 7.5 mg insulin for 3 to 12 months. Children randomized in the second block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 22.5 mg insulin for 3 to 12 months. Children randomized in the third block received placebo or 7.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 67.5 mg insulin for 3 to 12 months. Children randomized in the fourth block received placebo or 22.5 milligrams insulin dose for 3 to 12 months. Children randomized in the fifth block received placebo or 67.5 milligrams insulin dose for 3 to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The IMP was administered to the children in the following doses: 2.5 mg, 7.5 mg, 22.5 mg and 67.5 mg. The contents of one capsule were administered once a day, recommended at breakfast.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The contents of one capsule were administered once a day, recommended at breakfast.

    Number of subjects in period 1
    		Insulin Placebo
    Started
    15
    10
    Completed
    14
    9
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin
    Reporting group description
    		 The study randomized in study blocks of 5 participants. Children randomized in the first block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 7.5 mg insulin for 3 to 12 months. Children randomized in the second block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 22.5 mg insulin for 3 to 12 months. Children randomized in the third block received placebo or 7.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 67.5 mg insulin for 3 to 12 months. Children randomized in the fourth block received placebo or 22.5 milligrams insulin dose for 3 to 12 months. Children randomized in the fifth block received placebo or 67.5 milligrams insulin dose for 3 to 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Insulin Placebo Total
    Number of subjects
    		 15 10 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 15 10 25
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 7 8 15
        Male
    		 8 2 10
    Subject analysis sets

    Subject analysis set title
    Insulin 2.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 2.5 mg.

    Subject analysis set title
    Insulin 7.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 7.5 mg.

    Subject analysis set title
    Insulin 22.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 22.5 mg.

    Subject analysis set title
    Insulin 67.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 67.5 mg.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving placebo.

    Subject analysis sets values
    		 Insulin 2.5 mg Insulin 7.5 mg Insulin 22.5 mg Insulin 67.5 mg Placebo
    Number of subjects
    6
    6
    6
    6
    10
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
        Children (2-11 years)
    6
    6
    6
    6
    10
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Insulin
    Reporting group description
    		 The study randomized in study blocks of 5 participants. Children randomized in the first block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 7.5 mg insulin for 3 to 12 months. Children randomized in the second block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 22.5 mg insulin for 3 to 12 months. Children randomized in the third block received placebo or 7.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 67.5 mg insulin for 3 to 12 months. Children randomized in the fourth block received placebo or 22.5 milligrams insulin dose for 3 to 12 months. Children randomized in the fifth block received placebo or 67.5 milligrams insulin dose for 3 to 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Insulin 2.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 2.5 mg.

    Subject analysis set title
    Insulin 7.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 7.5 mg.

    Subject analysis set title
    Insulin 22.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 22.5 mg.

    Subject analysis set title
    Insulin 67.5 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving insulin at a dose of 67.5 mg.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects receiving placebo.

    Primary: Development of immunity to insulin

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    End point title
    		 Development of immunity to insulin
    End point description
    Antibody or T cell responses to insulin were observed during treatment.
    End point type
    Primary
    End point timeframe
    From baseline to a maximum of 18 months of treatment
    End point values
    		 Insulin 2.5 mg Insulin 7.5 mg Insulin 22.5 mg Insulin 67.5 mg Placebo
    Number of subjects analysed
    6
    6
    6
    6
    10
    Units: subject
    1
    1
    2
    5
    2
    Statistical analysis title
    		 Test for trend
    Comparison groups
    Insulin 2.5 mg v Insulin 7.5 mg v Insulin 22.5 mg v Insulin 67.5 mg v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.017
    Method
    		 Chi-squared test for trend
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Insulin
    Reporting group description
    		 The study randomized in study blocks of 5 participants. Children randomized in the first block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 7.5 mg insulin for 3 to 12 months. Children randomized in the second block received placebo or 2.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 22.5 mg insulin for 3 to 12 months. Children randomized in the third block received placebo or 7.5 milligrams insulin dose for 6 months followed by a dose escalation to placebo or 67.5 mg insulin for 3 to 12 months. Children randomized in the fourth block received placebo or 22.5 milligrams insulin dose for 3 to 12 months. Children randomized in the fifth block received placebo or 67.5 milligrams insulin dose for 3 to 12 months.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Insulin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Otitis media
    Additional description: The subject has had recurring events of otits media in the context of common colds with effusion (OME). The proband underwent surgery for 1. tonsillectomy, 2. adenoidectomy, 3. paracentesis with insertion of tympanostomy tubes.
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Insulin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 15 (80.00%)
    10 / 10 (100.00%)
    General disorders and administration site conditions
    Common cold
         subjects affected / exposed
    6 / 15 (40.00%)
    3 / 10 (30.00%)
         occurrences all number
    31
    6
    Immune system disorders
    Allergy symptoms
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 10 (10.00%)
         occurrences all number
    7
    2
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 10 (20.00%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 10 (10.00%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2009
    Change of sponsor
    27 May 2009
    Expansion of inclusion age
    18 Dec 2009
    primary oral insulin use; change of randomisation 3:1 to 3:2 (active to control arm(s)); deletion of active and control arm B; reduction of planned participant number from 40 to 25
    12 Dec 2012
    Removal of Canadian and of Italian trial sites; less restricted HLA genotype criteria for eligibility

    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/18445349
    http://www.ncbi.nlm.nih.gov/pubmed/18777449
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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
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