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    Clinical Trial Results:
    An exploratory Phase II Study to demonstrate the Safety and Efficacy of A4250 in Children with Cholestatic Pruritus

    Summary
    EudraCT number
    2015-001157-32
    Trial protocol
    SE   DK   DE   GB  
    Global end of trial date
    05 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A4250-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02630875
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Albireo AB
    Sponsor organisation address
    Arvid Wallgrens Backe 20, Göteborg, Sweden, 413 46
    Public contact
    Albireo AB , Albireo AB, 0046 31 741 14 80, info@albireopharma.com
    Scientific contact
    Responsible Medical Officer, Albireo AB, 0046 703747175, mats.ekelund@albireopharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002054-PIP01-16
    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
    31 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •Assess the safety and tolerability of A4250, orally administered •Explore changes in serum total bile acids
    Protection of trial subjects
    Each patient made 6 visits to the clinic where the patient was observed for safety variables and laboratory measurements. Physical examination and measurement of vital signs were done at each visit. Each patient received a patient diary to record symptoms during the study. Concomitant medication and any adverse events were collected at each visit. The study was designed to have six dose cohorts but during the Data Safety Monitoring Board (DSMB) meeting after the fifth cohort (0.2 mg/kg/day), based on a mean increase in ALT, the DSMB recommended that dosing at the same level could continue, but further dose escalation should be discontinued. A sixth cohort was enrolled, but these patients were treated at lower doses.
    Background therapy
    There were no general background therapy, but the patients were allowed to be on UDCA and rifampicin during the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Aug 2015
    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: 2
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    3
    Children (2-11 years)
    17
    Adolescents (12-17 years)
    4
    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
    The study was performed in cohorts followed by a DSMB meeting and decision prior to the start of next cohort. 6 sites participated in Sweden, Denmark, France and Germany. The first patient in was 25 Aug 2015, and last patient out was 17 Mar 2017. The 24 total subjects include 4 subjects who reenrolled and participated in two different dose groups.

    Pre-assignment
    Screening details
    Main inclusion criteria was children with cholestatic pruritus and elevated serum bile acids. Eligible patients made 6 site visits. Study baseline was defined as the last assessment prior to administration of the single dose at Visit 2. Patients were allowed to be re-enrolled into a second dose group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Baseline Dose Group 1: 0.01 mg/kg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    A4250
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One single oral dose was given at Visit 2, followed by at least 14 days wash-out. Eligible patients then received daily oral dosing for 4 weeks, starting at Visit 4.

    Arm title
    Baseline Dose Group 2: 0.03 mg/kg
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Baseline Dose Group 3: 0.06 mg/kg
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Baseline Dose Group 4: 0.1 mg/kg
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Baseline Dose group 5: 0.2 mg/kg
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg
    Started
    4
    6
    4
    6
    4
    Completed
    4
    6
    4
    6
    4
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment Dose Group 1: 0.01 mg/kg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    A4250
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One single oral dose was given at Visit 2, followed by at least 14 days wash-out. Eligible patients then received daily oral dosing for 4 weeks, starting at Visit 4.

    Arm title
    Treatment Dose Group 2: 0.03 mg/kg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    A4250
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One single oral dose was given at Visit 2, followed by at least 14 days wash-out. Eligible patients then received daily oral dosing for 4 weeks, starting at Visit 4.

    Arm title
    Treatment Dose Group 3: 0.06 mg/kg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    A4250
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One single oral dose was given at Visit 2, followed by at least 14 days wash-out. Eligible patients then received daily oral dosing for 4 weeks, starting at Visit 4.

    Arm title
    Treatment Dose Group 4: 0.1 mg/kg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    A4250
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One single oral dose was given at Visit 2, followed by at least 14 days wash-out. Eligible patients then received daily oral dosing for 4 weeks, starting at Visit 4.

    Arm title
    Treatment Dose Group 5: 0.2 mg/kg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    A4250
    Investigational medicinal product code
    A4250
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    One single oral dose was given at Visit 2, followed by at least 14 days wash-out. Eligible patients then received daily oral dosing for 4 weeks, starting at Visit 4.

    Number of subjects in period 2
    Treatment Dose Group 1: 0.01 mg/kg Treatment Dose Group 2: 0.03 mg/kg Treatment Dose Group 3: 0.06 mg/kg Treatment Dose Group 4: 0.1 mg/kg Treatment Dose Group 5: 0.2 mg/kg
    Started
    4
    6
    4
    6
    4
    Completed
    4
    6
    4
    6
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline Dose Group 1: 0.01 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose Group 2: 0.03 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose Group 3: 0.06 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose Group 4: 0.1 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose group 5: 0.2 mg/kg
    Reporting group description
    -

    Reporting group values
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg Total
    Number of subjects
    4 6 4 6 4 24
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 1 0 2 3
        Children (2-11 years)
    3 5 2 6 1 17
        Adolescents (12-17 years)
    1 1 1 0 1 4
        Adults (18-64 years)
    0 0 0 0 0 0
        From 65-84 years
    0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    1 5 1 2 0 9
        Male
    3 1 3 4 4 15
    Diagnosis
    Units: Subjects
        PFIC-1
    0 0 1 1 0 2
        PFIC-2
    0 2 2 3 2 9
        PFIC-3
    0 1 0 1 0 2
        Alagille-syndrome
    3 0 1 0 2 6
        Biliary atresia
    0 3 0 0 0 3
        Intrahepatic cholestasis microvillous athrophy
    1 0 0 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Baseline Dose Group 1: 0.01 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose Group 2: 0.03 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose Group 3: 0.06 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose Group 4: 0.1 mg/kg
    Reporting group description
    -

    Reporting group title
    Baseline Dose group 5: 0.2 mg/kg
    Reporting group description
    -
    Reporting group title
    Treatment Dose Group 1: 0.01 mg/kg
    Reporting group description
    -

    Reporting group title
    Treatment Dose Group 2: 0.03 mg/kg
    Reporting group description
    -

    Reporting group title
    Treatment Dose Group 3: 0.06 mg/kg
    Reporting group description
    -

    Reporting group title
    Treatment Dose Group 4: 0.1 mg/kg
    Reporting group description
    -

    Reporting group title
    Treatment Dose Group 5: 0.2 mg/kg
    Reporting group description
    -

    Primary: Summary of liver biochemistry: Total bile acids (umol/L)

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    End point title
    Summary of liver biochemistry: Total bile acids (umol/L) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Change from Study Baseline (Visit 1) to End of 4-week Treatment (Visit 5)
    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: All statistics in the study were descriptive.
    End point values
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg Treatment Dose Group 1: 0.01 mg/kg Treatment Dose Group 2: 0.03 mg/kg Treatment Dose Group 3: 0.06 mg/kg Treatment Dose Group 4: 0.1 mg/kg Treatment Dose Group 5: 0.2 mg/kg
    Number of subjects analysed
    4
    6
    4
    6
    4
    4
    6
    4
    6
    4
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    217.8 ± 100.67
    216 ± 177.29
    220.5 ± 159.99
    288.5 ± 126.83
    213.2 ± 236.61
    151.4 ± 146.26
    69.4 ± 42.11
    61.9 ± 64.22
    163.6 ± 165.81
    107 ± 150.01
    No statistical analyses for this end point

    Secondary: Summary of Daily Questionnaire: VAS Itching

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    End point title
    Summary of Daily Questionnaire: VAS Itching
    End point description
    End point type
    Secondary
    End point timeframe
    Change from Study Baseline (7 days prior to Visit 2) to End of 4-week Treatment (7 days before end of treatment including Visit 5).
    End point values
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg Treatment Dose Group 1: 0.01 mg/kg Treatment Dose Group 2: 0.03 mg/kg Treatment Dose Group 3: 0.06 mg/kg Treatment Dose Group 4: 0.1 mg/kg Treatment Dose Group 5: 0.2 mg/kg
    Number of subjects analysed
    4
    5
    4
    6
    4
    4
    6
    4
    6
    4
    Units: VAS score
        number (not applicable)
    5.9
    6.1
    5
    7.5
    6.1
    4.3
    3.6
    3.1
    4.7
    3.9
    No statistical analyses for this end point

    Secondary: Summary of Daily Questionnaire: PO-SCORAD Itching

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    End point title
    Summary of Daily Questionnaire: PO-SCORAD Itching
    End point description
    End point type
    Secondary
    End point timeframe
    Change from Study Baseline (7 days prior to Visit 2) to End of 4-week Treatment (7 days before end of treatment including Visit 5).
    End point values
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg Treatment Dose Group 1: 0.01 mg/kg Treatment Dose Group 2: 0.03 mg/kg Treatment Dose Group 3: 0.06 mg/kg Treatment Dose Group 4: 0.1 mg/kg Treatment Dose Group 5: 0.2 mg/kg
    Number of subjects analysed
    4
    5
    3
    6
    4
    4
    5
    4
    6
    4
    Units: PO-SCORAD score
        number (not applicable)
    5.1
    5.6
    5.2
    7.3
    5.8
    4
    3.5
    3
    4.5
    3.5
    No statistical analyses for this end point

    Secondary: Summary of Daily Questionnaire: Whitington Scale

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    End point title
    Summary of Daily Questionnaire: Whitington Scale
    End point description
    End point type
    Secondary
    End point timeframe
    Change from Study Baseline (7 days prior to Visit 2) to End of 4-week Treatment (7 days before end of treatment including Visit 5).
    End point values
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg Treatment Dose Group 1: 0.01 mg/kg Treatment Dose Group 2: 0.03 mg/kg Treatment Dose Group 3: 0.06 mg/kg Treatment Dose Group 4: 0.1 mg/kg Treatment Dose Group 5: 0.2 mg/kg
    Number of subjects analysed
    4
    5
    4
    6
    4
    4
    6
    4
    6
    4
    Units: Whitington score
        number (not applicable)
    2.3
    2.2
    2.9
    3.5
    2
    2.3
    1.5
    1.3
    2.1
    1.5
    No statistical analyses for this end point

    Secondary: Summary of Daily Questionnaire: PO-SCORAD Sleep

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    End point title
    Summary of Daily Questionnaire: PO-SCORAD Sleep
    End point description
    End point type
    Secondary
    End point timeframe
    Change from Study Baseline (7 days prior to Visit 2) to End of 4-week Treatment (7 days before end of treatment including Visit 5).
    End point values
    Baseline Dose Group 1: 0.01 mg/kg Baseline Dose Group 2: 0.03 mg/kg Baseline Dose Group 3: 0.06 mg/kg Baseline Dose Group 4: 0.1 mg/kg Baseline Dose group 5: 0.2 mg/kg Treatment Dose Group 1: 0.01 mg/kg Treatment Dose Group 2: 0.03 mg/kg Treatment Dose Group 3: 0.06 mg/kg Treatment Dose Group 4: 0.1 mg/kg Treatment Dose Group 5: 0.2 mg/kg
    Number of subjects analysed
    4
    5
    3
    6
    4
    4
    5
    4
    6
    4
    Units: PO-SCORAD Sleep Score
        number (not applicable)
    4
    4.4
    4.9
    7.3
    5
    4
    2.7
    2.6
    4.3
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were to be collected throughout the study beginning at the time the patient had signed the ICF.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Dose group 1: 0.01 mg/kg
    Reporting group description
    -

    Reporting group title
    Dose group 2: 0.03 mg/kg
    Reporting group description
    -

    Reporting group title
    Dose group 3: 0.06 mg/kg
    Reporting group description
    -

    Reporting group title
    Dose group 4: 0.1 mg/kg
    Reporting group description
    -

    Reporting group title
    Dose group 5: 0.2 mg/kg
    Reporting group description
    -

    Serious adverse events
    Dose group 1: 0.01 mg/kg Dose group 2: 0.03 mg/kg Dose group 3: 0.06 mg/kg Dose group 4: 0.1 mg/kg Dose group 5: 0.2 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dose group 1: 0.01 mg/kg Dose group 2: 0.03 mg/kg Dose group 3: 0.06 mg/kg Dose group 4: 0.1 mg/kg Dose group 5: 0.2 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 6 (50.00%)
    4 / 4 (100.00%)
    2 / 6 (33.33%)
    4 / 4 (100.00%)
    Injury, poisoning and procedural complications
    Traumatic haematoma
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Toxicity to various agents
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Respiratory moniliasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    0
    4
    Hyperthermia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Perineal erythema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Xanthochromia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Bronchitis bacterial
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2015
    Only applicable for France: - Administration immediately after mixing A4250 into food - Nasogastric tube deleted - Washout period (min 95 days) added - Filling of capsules clarified - Blood sample schedule added
    02 Mar 2016
    - Mats Ekelund as director of medicine to replace Hans Graffner (deceased) - Creatine Kinase (CK) added in Routine clinical chemistry - Additional cohorts after dose escalation stop (substantial amendment)
    01 Sep 2016
    Only applicable for Sweden: - Age inclusion criteria changed from 18 to 26 years
    13 Oct 2016
    Only applicable for the United Kingdom: - Concurrent medications prohibited during the study - Correction of the definition of child bearing potential

    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.
    Patients completing Cohort 1 could re-enter the study in one of the Cohorts 4, 5 or 6. Patients completing Cohort 2 could re-enter Cohorts 5 or 6 and patients completing Cohort 3 could re-enter Cohort 6. Re-enrolled required new signature of ICF.
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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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