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    Clinical Trial Results:
    A Randomized, Controlled, Open-label, Multicenter, Phase IIb Safety and Efficacy Study of HGT-1410 (Recombinant Human Heparan N Sulfatase) Administration via an Intrathecal Drug Delivery Device in Pediatric Patients with Early Stage

    Summary
    EudraCT number
    2013-003450-24
    Trial protocol
    DE   GB   ES   NL   IT   FR  
    Global end of trial date
    01 Jun 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Dec 2016
    First version publication date
    17 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-SAN-093
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02060526
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Human Genetic Therapies, Inc
    Sponsor organisation address
    300 Shire Way, Lexington, MA, United States, 02421
    Public contact
    Study Physician, Shire, 1 866-842-5335,
    Scientific contact
    Study Physician, Shire, 1 866-842-5335,
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the potential clinical efficacy of HGT-1410 (Recombinant Human Heparan N Sulfatase) administered using a surgically implanted intrathecal drug delivery device (IDDD) in subjects with Sanfilippo Syndrome Type A.
    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
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Feb 2014
    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
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Netherlands: 2
    Worldwide total number of subjects
    21
    EEA total number of subjects
    14
    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)
    4
    Children (2-11 years)
    17
    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
    A total of 24 subjects were screened, of them 21 subjects were enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    No HGT-1410
    Arm description
    Subjects received no treatment (HGT-1410).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    HGT-1410 45 mg Q2W
    Arm description
    Subjects received HGT-1410 45 milligram (mg) intrathecally once every two weeks (Q2W) using surgically implanted intrathecal drug delivery device (IDDD) or lumbar puncture (LP) for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant Human Heparan N-Sulfatase
    Investigational medicinal product code
    HGT-1410
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received 45 mg HGT-1410 intrathecally.

    Arm title
    HGT-1410 45 mg Q4W
    Arm description
    Subjects received HGT-1410 45 mg intrathecally once every four weeks (Q4W) using surgically implanted IDDD or LP for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant Human Heparan N-Sulfatase
    Investigational medicinal product code
    HGT-1410
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received 45 mg HGT-1410 intrathecally.

    Number of subjects in period 1
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Started
    7
    7
    7
    Completed
    7
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    No HGT-1410
    Reporting group description
    Subjects received no treatment (HGT-1410).

    Reporting group title
    HGT-1410 45 mg Q2W
    Reporting group description
    Subjects received HGT-1410 45 milligram (mg) intrathecally once every two weeks (Q2W) using surgically implanted intrathecal drug delivery device (IDDD) or lumbar puncture (LP) for 48 weeks.

    Reporting group title
    HGT-1410 45 mg Q4W
    Reporting group description
    Subjects received HGT-1410 45 mg intrathecally once every four weeks (Q4W) using surgically implanted IDDD or LP for 48 weeks.

    Reporting group values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W Total
    Number of subjects
    7 7 7
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: months
        arithmetic mean (standard deviation)
    32.42 ± 9.548 29.64 ± 9.989 33.53 ± 9.336 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    3 5 4 12
        Male
    4 2 3 9

    End points

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    End points reporting groups
    Reporting group title
    No HGT-1410
    Reporting group description
    Subjects received no treatment (HGT-1410).

    Reporting group title
    HGT-1410 45 mg Q2W
    Reporting group description
    Subjects received HGT-1410 45 milligram (mg) intrathecally once every two weeks (Q2W) using surgically implanted intrathecal drug delivery device (IDDD) or lumbar puncture (LP) for 48 weeks.

    Reporting group title
    HGT-1410 45 mg Q4W
    Reporting group description
    Subjects received HGT-1410 45 mg intrathecally once every four weeks (Q4W) using surgically implanted IDDD or LP for 48 weeks.

    Primary: Overall Assessment of Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III)

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    End point title
    Overall Assessment of Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III)
    End point description
    The BSID­III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The DQ is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0, 100). The BSID­III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Overall response was the maximum decline in the development quotient (DQ) of 10 points or less over 48 weeks. Number of subjects with the overall response were reported here. Intent-to-treat population included all randomized participants was analysed for this end point.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) up to Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: subjects
    0
    2
    1
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    95% exact unconditional confidence interval of the difference in proportion between each of the treatment groups and the untreated control group was considered for the parameter estimation.
    Comparison groups
    HGT-1410 45 mg Q2W v No HGT-1410
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4615
    Method
    Fisher exact
    Parameter type
    Difference between proportions
    Point estimate
    0.286
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.297
         upper limit
    0.745
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    95% exact unconditional confidence interval of the difference in proportion between each of the treatment groups and the untreated control group was considered for the parameter estimation.
    Comparison groups
    No HGT-1410 v HGT-1410 45 mg Q4W
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Difference between proportions
    Point estimate
    0.143
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.423
         upper limit
    0.647

    Secondary: Number of Subjects With Serious Adverse Events (SAE)

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    End point title
    Number of Subjects With Serious Adverse Events (SAE)
    End point description
    An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all subjects who received a dose of HGT-1410 either using IDDD implantation or LP; underwent the IDDD surgical implant procedure without receiving a dose of HGT-1410; were randomly assigned to the untreated group and had any safety follow-up data was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: subjects
    3
    5
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. TEAEs were defined as AE occurring on or after the time of first IDDD implantation or LP procedure to the end of study (EOS) visit (+30 days). Safety population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: subjects
    6
    7
    7
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48

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    End point title
    Number of Subjects With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48
    End point description
    A subject was considered positive if they had at least 1 positive result during the study. Once a subject reported antibody positive, they were considered positive for the remainder of the study. Safety population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: subjects
    1
    7
    6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48

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    End point title
    Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). A positive value indicates improvement in health and cognition. Intent-to-treat population included randomized subjects were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: percentage of chronological age
    arithmetic mean (standard deviation)
        Communication Domain (n=7,6,7)
    -5.12 ± 10.981
    -20.83 ± 23.475
    -4.97 ± 17.253
        Daily Living Skills Domain (n=6,6,6)
    -4.2 ± 29.005
    -27.09 ± 21.444
    -11.74 ± 26.713
        Socialization Domain (n=6,6,6)
    -16.12 ± 23.32
    -24.24 ± 40.617
    -29.34 ± 29.425
        Motor Skills Domain (n=6,6,6)
    -5.37 ± 24.741
    -27.01 ± 20.82
    -17.88 ± 12.007
    No statistical analyses for this end point

    Secondary: Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48

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    End point title
    Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48
    End point description
    The BSID­III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The DQ is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0, 100). The BSID-III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Intent-to-treat population included randomized subjects were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: percentage of chronological age
    arithmetic mean (standard deviation)
        Cognitive
    -19.81 ± 3.974
    -23.82 ± 14.684
    -19.87 ± 12.724
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Cortical Grey Matter Volume at Week 48

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    End point title
    Change from Baseline in Total Cortical Grey Matter Volume at Week 48
    End point description
    The change from baseline in grey matter volume at Week 48 was assessed by magnetic resonance imaging (MRI). Intent-to-treat population included randomized subjects were analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    7
    Units: cubic centimeter (cc)
        arithmetic mean (standard deviation)
    -45.1 ± 23.35
    -102 ± 68.12
    -58.8 ± 66.24
    No statistical analyses for this end point

    Secondary: Change from Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48

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    End point title
    Change from Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48
    End point description
    Change from baseline in concentration of GAG in CSF at Week 48 was reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    4
    7
    7
    Units: micromolar
        arithmetic mean (standard deviation)
    -0.193 ± 1.318
    -6.888 ± 5.388
    -5.924 ± 2.47
    No statistical analyses for this end point

    Secondary: Change from Baseline in Concentration of GAG in Urine at Week 48

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    End point title
    Change from Baseline in Concentration of GAG in Urine at Week 48
    End point description
    The concentration of GAG in urine was normalized to the urine creatinine value and reported as milligram (mg) GAG per millimole (mmol) creatinine. ITT population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 48
    End point values
    No HGT-1410 HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    5
    7
    5
    Units: mg GAG/mmol creatinine
        arithmetic mean (standard deviation)
    -7.18 ± 39.175
    -31.81 ± 22.887
    -42.46 ± 29.861
    No statistical analyses for this end point

    Secondary: Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF)

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    End point title
    Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) [1]
    End point description
    Concentration of rhHNS in CSF was assessed using validated enzyme-linked immunosorbent assay (ELISA) method. Pharmacokinetic (PK) population included all subjects who received HGT-1410, participated in the scheduled PK studies, and had sufficient samples available for analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 4, 48 hours on Week 0 and Week 48
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic analysis was performed for the arms which received the drug only.
    End point values
    HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    Units: nanogram per milliliter (ng/ml)
    arithmetic mean (standard deviation)
        Week 0: Predose (n=7,7)
    0 ± 0
    0 ± 0
        Week 0: 4h (n=5,5)
    313392.49 ± 142748.885
    266021.6 ± 113340.887
        Week 0: 48h (n=6,6)
    366.05 ± 571.528
    2119.59 ± 2068.093
        Week 48: Predose (n=6,7)
    869.67 ± 1863.989
    365.04 ± 965.797
        Week 48: 4h (n=5,5)
    374544.38 ± 135047.7
    335203.84 ± 82918.537
        Week 48: 48h (n=4,5)
    104.49 ± 65.881
    8892.93 ± 19519.717
    No statistical analyses for this end point

    Secondary: Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in serum

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    End point title
    Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in serum [2]
    End point description
    Cmax of rhHNS in serum was evaluated using enzyme-linked immunosorbent assay (ELISA) method and liquid chromatography tandem mass spectrometry (LC-MS) method. Pharmacokinetic (PK) population was analysed for this end point.
    End point type
    Secondary
    End point timeframe
    Predose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h post-dose on Week 0 and Week 48
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic analysis was performed for the arms which received the drug only.
    End point values
    HGT-1410 45 mg Q2W HGT-1410 45 mg Q4W
    Number of subjects analysed
    7
    7
    Units: ng/ml
    arithmetic mean (standard deviation)
        ELISA Method: Week 0 (n=7,7)
    120.9 ± 84.77
    237 ± 159.68
        ELISA Method: Week 48 (n=7,4)
    63.5 ± 149.76
    118.8 ± 161.98
        LC-MS Method: Week 0 (n=7,7)
    102.4 ± 63
    191 ± 125.84
        LC-MS Method: Week 48 (n=7,5)
    188.1 ± 127.4
    119.7 ± 133.18
    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 Week 52
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    No HGT-1410
    Reporting group description
    Subjects received no treatment (HGT-1410).

    Reporting group title
    HGT-1410 45 mg Q4W
    Reporting group description
    Subjects received HGT-1410 45 mg intrathecally Q4W using surgically implanted IDDD or LP for 48 weeks.

    Reporting group title
    HGT-1410 45 mg Q2W
    Reporting group description
    Subjects received HGT-1410 45 mg intrathecally Q2W using surgically implanted IDDD or LP for 48 weeks.

    Serious adverse events
    No HGT-1410 HGT-1410 45 mg Q4W HGT-1410 45 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    6 / 7 (85.71%)
    5 / 7 (71.43%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Incision site swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device breakage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site extravasation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Central nervous system infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    No HGT-1410 HGT-1410 45 mg Q4W HGT-1410 45 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    Vascular disorders
    Diastolic hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Diastolic hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    Systolic hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Developmental delay
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Impaired healing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Implant site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Implant site extravasation
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    1
    Implant site swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Local swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    4 / 7 (57.14%)
    4 / 7 (57.14%)
    4 / 7 (57.14%)
         occurrences all number
    10
    5
    22
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Agitation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Irritability
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    Sleep terror
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Vulvovaginal erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Airway complication of anaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    Craniocerebral injury
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Incision site complication
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
         occurrences all number
    1
    1
    3
    Limb injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Postoperative fever
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Procedural dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Procedural headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    1
    0
    4
    Procedural hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Subdural haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    1
    Stab wound
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Wound complication
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Blood pressure decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Blood pressure diastolic decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    1
    5
    0
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Blood pressure systolic decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    1
    10
    0
    Crystal urine present
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Body temperature decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    Csf test abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Csf protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Csf white blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    2
    Heart rate decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    1
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    8
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    5
    Platelet count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    2
    Protein total increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory rate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Urine uric acid
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    2
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Nasal obstruction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    1
    Sinus disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Cerebral atrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Cognitive disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Demyelination
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Drooling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    2
    Motor dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Motion sickness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Otorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    1
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    2
    Enteritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    4
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Salivary gland enlargement
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    2
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 7 (42.86%)
    5 / 7 (71.43%)
         occurrences all number
    2
    4
    12
    Salivary hypersecretion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Mucocutaneous rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Pityriasis rosea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    2
    Rash macular
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Rickets
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Vitamin d deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    3
    Ear infection
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 7 (57.14%)
    0 / 7 (0.00%)
         occurrences all number
    3
    6
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    2
    Implant site infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    2
    Hand-Foot-And-Mouth disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Meningitis aseptic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    6
    4
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Otitis media acute
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
         occurrences all number
    0
    1
    3
    Pharyngitis
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    3
    Rhinitis
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
         occurrences all number
    3
    2
    4
    Scarlet fever
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    Stitch abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea pedis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis streptococcal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    5 / 7 (71.43%)
         occurrences all number
    6
    2
    18
    Tooth abscess
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2014
    - Permitted subjects in the United States (US) to receive Intrathecal (IT) treatment with HGT-1410 by LP prior to FDA authorization of use of the SOPH-A-PORT Mini S device. - Removed the Sanfilippo-specific Behavioral Rating Scales as an evaluative tool. - Removed collection of plasma samples for exploratory investigation of biomarkers. - Required vital sign measurements to be recorded for at least 4 hours following each dose of HGT-1410. - Prothrombin time and activated partial thromboplastin time were to be performed at screening only. - Removed requirement for predose CSF cell counts to be available before study drug administration. - Updated the definition of the safety population to include subjects in the US who were treated with HGT-1410 via LP until the IDDD is available. - Limited the number of pharmacokinetic samples taken to reduce overall blood volume requirements. - Added appendices detailing blood and CSF volumes taken from each subject at each time pint and overall.
    15 Jul 2014
    - Removed language to allow administration of study drug by LP in the US until the IDDD is authorized for use by the FDA. - Clarified criterion for demonstrating deficiency of sulfamidase. - Clarified that use of catheter passers other than Phoenix Neuro disposable catheter passer were allowed. - Clarified that heparan sulfate was to be measured in CSF as opposed to total GAGs. - Added language to indicate that CSF may be assessed for leachables or extractables. - Clarified that MRI was to be performed prior to the administration of HGT-1410.
    08 Sep 2014
    - Removed the Week 24 MRI assessment and collection of CSF by LP. - Clarified that the follow-up safety visit only applied to those subjects not continuing into extension study SHP -610-201 (2014-003960-20 ). - Clarified that CSF sample collection for GAG would occur 4 hours (not 6 hours) after IT injection.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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