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    Clinical Trial Results:
    An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and Efficacy Study of HGT-1410 (Recombinant Human Heparan N Sulfatase) Administration via an Intrathecal Drug Delivery Device in Pediatric Subjects with Mucopolysaccharidosis Type IIIA Disease

    Summary
    EudraCT number
    2014-003960-20
    Trial protocol
    ES   DE   NL   GB   FR   IT  
    Global end of trial date
    12 Apr 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Jun 2020
    First version publication date
    21 Sep 2019
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP610-201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02350816
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, 1 8668425335, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, 1 8668425335, ClinicalTransparency@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001634-PIP01-14
    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
    Interim
    Date of interim/final analysis
    28 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate long-term safety in subjects with mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo Type A) who received HGT-1410.
    Protection of trial subjects
    This study was designed to ensure that the sponsor and investigators abided by Good Clinical Practice (GCP) as described in the 21 Code of Federal Regulations Parts 50, 54, 56, and 312 and the International Council for Harmonisation (ICH) GCP Guidelines Compliance. These regulations and guidelines also constitute compliance with the ethical principles described in the Declaration of Helsinki.
    Background therapy
    Subjects who received HGT-1410 and completed through at least the Week 48 visit in Study HGT-SAN-093 (2013-003450-24) were eligible in this open label extension study.
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    17
    EEA total number of subjects
    11
    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)
    14
    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
    The first subject enrolled in the study on 08 April 2015 and study terminated on 28 June 2017.

    Pre-assignment
    Screening details
    A total of 17 subjects were enrolled and completed treatment period in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 milligrams (mg) administered intrathecally (IT) via IT drug delivery device (IDDD) every 2 weeks (Q2W) started at Week 50, with a cumulative treatment period of up to 42 months (168 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    HGT-1410
    Investigational medicinal product code
    HGT-1410
    Other name
    Recombinant Human Heparan N Sulfatase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410 at a dose of 45 mg administered IT via IDDD.

    Arm title
    Group 2
    Arm description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 mg administered intrathecally IDDD every 4 weeks (Q4W) started at Week 52, with a cumulative treatment period of up to 42 months (168 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    HGT-1410
    Investigational medicinal product code
    HGT-1410
    Other name
    Recombinant Human Heparan N Sulfatase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410 at a dose of 45 mg administered IT via IDDD.

    Arm title
    Group 3A
    Arm description
    Subjects in Group 3A were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally IDDD Q2W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    HGT-1410
    Investigational medicinal product code
    HGT-1410
    Other name
    Recombinant Human Heparan N Sulfatase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410 at a dose of 45 mg administered IT via IDDD.

    Arm title
    Group 3B
    Arm description
    Subjects in Group 3B were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally via IDDD Q4W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    HGT-1410
    Investigational medicinal product code
    HGT-1410
    Other name
    Recombinant Human Heparan N Sulfatase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410 at a dose of 45 mg administered IT via IDDD.

    Number of subjects in period 1
    Group 1 Group 2 Group 3A Group 3B
    Started
    7
    6
    2
    2
    Completed
    0
    0
    0
    0
    Not completed
    7
    6
    2
    2
         Subjects Who Completed Treatment Period
    7
    6
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 milligrams (mg) administered intrathecally (IT) via IT drug delivery device (IDDD) every 2 weeks (Q2W) started at Week 50, with a cumulative treatment period of up to 42 months (168 weeks).

    Reporting group title
    Group 2
    Reporting group description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 mg administered intrathecally IDDD every 4 weeks (Q4W) started at Week 52, with a cumulative treatment period of up to 42 months (168 weeks).

    Reporting group title
    Group 3A
    Reporting group description
    Subjects in Group 3A were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally IDDD Q2W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).

    Reporting group title
    Group 3B
    Reporting group description
    Subjects in Group 3B were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally via IDDD Q4W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).

    Reporting group values
    Group 1 Group 2 Group 3A Group 3B Total
    Number of subjects
    7 6 2 2
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29.64 ± 9.989 31.62 ± 8.598 40.40 ± 5.798 36.95 ± 7.142 -
    Gender categorical
    Units:
        Male
    2 3 0 2 7
        Female
    5 3 2 0 10
    Race (NIH/OMB)
    Units: Subjects
        White
    7 6 2 2 17
        Black or African American
    0 0 0 0 0
        Asian
    0 0 0 0 0
        American Indian or Native Alaskan
    0 0 0 0 0
        Native Hawaiian or other Pacific Islander
    0 0 0 0 0
        Other
    0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 1 0 0 1
        Not Hispanic or Latino
    7 5 2 2 16
        Not reported
    0 0 0 0 0
        Unknown
    0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 milligrams (mg) administered intrathecally (IT) via IT drug delivery device (IDDD) every 2 weeks (Q2W) started at Week 50, with a cumulative treatment period of up to 42 months (168 weeks).

    Reporting group title
    Group 2
    Reporting group description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 mg administered intrathecally IDDD every 4 weeks (Q4W) started at Week 52, with a cumulative treatment period of up to 42 months (168 weeks).

    Reporting group title
    Group 3A
    Reporting group description
    Subjects in Group 3A were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally IDDD Q2W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).

    Reporting group title
    Group 3B
    Reporting group description
    Subjects in Group 3B were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally via IDDD Q4W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).

    Primary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) Based on Type, Severity and Relationship to Treatment Drug

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    End point title
    Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) Based on Type, Severity and Relationship to Treatment Drug [1]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation subject administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. TEAEs was defined as all AEs from the time of initial IDDD implantation (or first dose if earlier) in either Study NCT02060526 (HGT-SAN-093) or Study NCT02350816 (SHP-610-210) to the data cutoff date (28 Jun 2017), or 30 days after the date of the last dose or 2 weeks after the date of device explant (whichever was later) if early termination occurred. Treatment-emergent AEs were summarized by type (serious, life-threatening), severity (mild, moderate, severe) and degree of relationship to investigational product (Intrathecal Drug Delivery Device (IDDD), device surgical procedure, or intraThecal administration of HGT-1410). Safety population consisted of all subjects who had the IDDD implant or received at least 1 dose of investigational product in the extension study
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to follow-up (276 week)
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Group 1 Group 2 Group 3A Group 3B
    Number of subjects analysed
    7
    6
    2
    2
    Units: Subjects
        Subjects with TEAEs
    7
    6
    2
    2
        Subjects with Serious TEAEs
    6
    6
    0
    1
        Subjects with Life-Threatening TEAEs
    0
    0
    0
    0
        Subjects with Mild TEAEs
    0
    0
    1
    1
        Subjects with Moderate TEAEs
    4
    4
    1
    1
        Subjects with Severe TEAEs
    3
    2
    0
    0
        Subjects with HGT-1410 Related TEAEs
    5
    5
    1
    1
        Subjects with Surgery Related TEAEs
    6
    6
    1
    1
        Subjects with IDDD Related TEAEs
    5
    6
    0
    1
        Subjects with IT Administration Related TEAEs
    3
    6
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to follow-up (124 week).
    Adverse event reporting additional description
    Event desc
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    nil
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 milligrams (mg) administered intrathecally (IT) via IT drug delivery device (IDDD) every 2 weeks (Q2W) started at Week 50, with a cumulative treatment period of up to 42 months (168 weeks).

    Reporting group title
    Group 2
    Reporting group description
    Subjects continued HGT-1410 treatment from HGT-SAN-093 (2013-003450-24) study at a dose of 45 mg administered intrathecally IDDD every 4 weeks (Q4W) started at Week 52, with a cumulative treatment period of up to 42 months (168 weeks).

    Reporting group title
    Group 3A
    Reporting group description
    Subjects in Group 3A were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally IDDD Q2W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).

    Reporting group title
    Group 3B
    Reporting group description
    Subjects in Group 3B were not treated in HGT-SAN-093 (2013-003450-24) study. Subjects received HGT-1410 treatment at a dose of 45mg administered intrathecally via IDDD Q4W started at Week 0 of the current extension study (SHP610-201=2014-003960-20), with a cumulative treatment period of up to 30 months (120 weeks).

    Serious adverse events
    Group 1 Group 2 Group 3A Group 3B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    6 / 6 (100.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Incision site swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 6 (66.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device breakage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site extravasation
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Central nervous system infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1 Group 2 Group 3A Group 3B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    2 / 2 (100.00%)
    2 / 2 (100.00%)
    Vascular disorders
    Diastolic hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diastolic hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Systolic hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Device malfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Impaired healing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Implant site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Implant site extravasation
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Implant site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Implant site swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Local swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Medical device pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    6 / 7 (85.71%)
    3 / 6 (50.00%)
    2 / 2 (100.00%)
    2 / 2 (100.00%)
         occurrences all number
    30
    6
    12
    5
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Decreased interest
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Irritability
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep terror
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Vulvovaginal erythema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Airway complication of anaesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    1
    1
    2
    Craniocerebral injury
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Face injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    4 / 7 (57.14%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
    1 / 2 (50.00%)
         occurrences all number
    4
    1
    1
    2
    Head injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Incision site complication
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Incision site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Postoperative fever
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural headache
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    5 / 7 (71.43%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    6
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Subdural haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Wound complication
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood folate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood pressure diastolic decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    5
    0
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    4
    0
    4
    Blood pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Blood pressure systolic decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    10
    0
    3
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    2
    0
    4
    Body temperature decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Body temperature increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    CSF protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    CSF test abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    CSF white blood cell count increased
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 6 (50.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Heart rate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    4
    0
    1
    Heart rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    7
    0
    6
    Neutrophil count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    4
    2
    0
    2
    Platelet count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Protein total increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Red blood cell count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory rate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urine uric acid
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    White blood cells urine positive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bronchospasm
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sinus disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cerebral atrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Demyelination
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Motor dysfunction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Ear and labyrinth disorders
    Motion sickness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otorrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    6
    1
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Enteritis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Salivary gland enlargement
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Umbilical hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    5 / 7 (71.43%)
    3 / 6 (50.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    14
    4
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mucocutaneous rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pityriasis rosea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchopneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 6 (66.67%)
    1 / 2 (50.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    6
    1
    1
    Folliculitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    6
    2
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Implant site infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Labyrinthitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    4
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    4 / 7 (57.14%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Otitis media acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    5 / 7 (71.43%)
    1 / 6 (16.67%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    11
    2
    1
    0
    Scarlet fever
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Stitch abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinea pedis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis streptococcal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 7 (85.71%)
    2 / 6 (33.33%)
    1 / 2 (50.00%)
    1 / 2 (50.00%)
         occurrences all number
    28
    5
    2
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Varicella
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    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
    17 Dec 2015
    Exclusion criteria on hypersensitivity were revised. Interim analysis were clarified device adjustment language was added to capture the full scope of device manipulations that could have occurred throughout the study.
    25 Jan 2017
    The subjects who did not have the IDDD removed at the end of the treatment period continued to be observed during a safety follow-up period with visits every 6 months to evaluate safety of the device for up to an additional 3 years or until the device was removed in the last subject.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated as prespecified efficacy criteria were not met and study did not yield clinical proof-of-concept, prompting a decision to discontinue further clinical development of HGT-1410. Hence efficacy parameters were not evaluated.
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