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    Clinical Trial Results:
    An Open-Label Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Iduronate-2-Sulfatase Enzyme Replacement Therapy

    Summary
    EudraCT number
    2004-002743-27
    Trial protocol
    DE   GB   SE   IT   ES  
    Global end of trial date
    31 Jan 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Sep 2018
    First version publication date
    25 Apr 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TKT024EXT
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00630747
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Human Genetic Therapies
    Sponsor organisation address
    700 Main Street, Cambridge, Massachusetts, United States, 02139
    Public contact
    Dr. Arian Pano, Medical Director, Shire Human Genetic Therapies, +1 781-482-0875, apano@shire.com
    Scientific contact
    Dr. Arian Pano, Medical Director, Shire Human Genetic Therapies, +1 781-482-0875, apano@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000294-PIP02-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this open-label extension study was to collect long-term safety and clinical outcome data in subjects with Mucopolysaccharidosis Type II (MPS II) or Hunter Syndrome who were receiving idursulfase (DRX006A) enzyme replacement therapy.
    Protection of trial subjects
    This study was conducted in accordance with local regulatory requirements, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and the ethical principles described in the current revision (2002) of Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Sep 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Germany: 18
    Worldwide total number of subjects
    94
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    34
    Adolescents (12-17 years)
    27
    Adults (18-64 years)
    33
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    TKT024EXT was designed to allow subjects in the double-blind phase of Study TKT024, a one year Phase 2/Phase 3 registration study, to continue long-term idursulfase therapy and to allow placebo subjects in TKT024 to receive active idursulfase treatment. The first subject enrolled on 13 Sep 2004. The study was conducted at 52 sites in 17 countrie

    Pre-assignment
    Screening details
    Subjects were screened for entry based on their known medical histories and previous participation in the TKT024 study. Subjects had to have completed Week 53 final evaluations in the TKT024 study. Subjects were not to have received any treatment with an investigational therapy other than idursulfase within 60 days of study entry.

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

    Arms
    Arm title
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Arm description
    Idursulfase 0.5 milligram per kilogram (mg/kg) administered by intravenous (IV) infusion once-weekly.
    Arm type
    Experimental

    Investigational medicinal product name
    Idursulfase
    Investigational medicinal product code
    DRX006A
    Other name
    Elaprase®, iduronate-2-sulfatase
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.

    Number of subjects in period 1
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Started
    94
    Subjects Treated in Phase I of Study
    94
    Completed
    85
    Not completed
    9
         Transferred to Study TKT031NPU
    7
         Death
    1
         'Returned to country of origin '
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Reporting group description
    Idursulfase 0.5 milligram per kilogram (mg/kg) administered by intravenous (IV) infusion once-weekly.

    Reporting group values
    Idursulfase (0.5 mg/kg, IV, Once-weekly) Total
    Number of subjects
    94 94
    Age categorical
    Units: Subjects
        <=18 years
    70 70
        Between 18 and 65 years
    24 24
        >=65 years
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.52 ± 6.634 -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    94 94
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    15 15
        Not Hispanic or Latino
    79 79
        Unknown or Not Reported
    0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    3 3
        Asian
    5 5
        Native Hawaiian or Other Pacific Islander
    0 0
        Black or African American
    6 6
        White
    78 78
        More than one race
    0 0
        Unknown or Not Reported
    2 2
    Baseline Percent Predicted Forced Vital Capacity (FVC)
    Units: percent predicted FVC
        arithmetic mean (standard deviation)
    56.16 ± 14.897 -
    Baseline Distance Walked in the 6-minute Walk Test (6MWT)
    Units: meters (m)
        arithmetic mean (standard deviation)
    400.3 ± 100.25 -
    Baseline Passive Joint Range of Motion (JROM)
    Global JROM (percentage (%) normal range of motion) is the average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive range of motion in Shoulder (Flexion/Extension, Abduction, Internal/External Rotation), Elbow (Flexion/Extension), Wrist (Flexion/Extension), Index Finger (Flexion/Extension [Combined MCP, PIP, DIP motion]), Hip (Flexion/Extension, Abduction, Internal/External Rotation), Knee (Flexion/Extension), and Ankle (Dorsiflexion) divided by the normal range (American Academy of Orthopedic Surgeons and American Medical Association).
    Units: percentage
        arithmetic mean (standard deviation)
    67.44 ± 9.042 -
    Baseline Combined Liver and Spleen Volume
    Units: cubic centimeters (cc)
        arithmetic mean (standard deviation)
    1504.8 ± 417.21 -
    Baseline Normalized Urine Glycosaminoglycans (GAG) Levels
    Units: microgram(mcg)GAG/mg creatinine
        arithmetic mean (standard deviation)
    361.96 ± 136.132 -
    Baseline Cardiac Left Ventricular Mass Index (LVMI)
    Units: Gram per meter^2 (g/m^2)
        arithmetic mean (standard deviation)
    97.64 ± 36.606 -

    End points

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    End points reporting groups
    Reporting group title
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Reporting group description
    Idursulfase 0.5 milligram per kilogram (mg/kg) administered by intravenous (IV) infusion once-weekly.

    Primary: Change From Baseline in Mean Percent Predicted Forced Vital Capacity (FVC) at Week 105

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    End point title
    Change From Baseline in Mean Percent Predicted Forced Vital Capacity (FVC) at Week 105 [1]
    End point description
    Determined by spirometry. The change was calculated as Week 105 minus baseline. All subjects for whom percent predicted FVC were recorded at baseline and at Week 105.
    End point type
    Primary
    End point timeframe
    Baseline and at Week 105
    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 statistical analysis was only performed and inferential statistical analysis was not performed for this endpoint.
    End point values
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Number of subjects analysed
    85
    Units: percent predicted FVC
        arithmetic mean (standard error)
    -0.056 ± 1.059
    No statistical analyses for this end point

    Primary: Change From Baseline in Mean Distance Walked in the 6-minute Walk Test (6MWT) at Week 105

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    End point title
    Change From Baseline in Mean Distance Walked in the 6-minute Walk Test (6MWT) at Week 105 [2]
    End point description
    Determined on a walking course. The change was calculated as Week 105 minus baseline. All subjects for whom distance walked was recorded at baseline and at Week 105.
    End point type
    Primary
    End point timeframe
    Baseline and at Week 105
    Notes
    [2] - 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 statistical analysis was only performed and inferential statistical analysis was not performed for this endpoint.
    End point values
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Number of subjects analysed
    85
    Units: meters
        arithmetic mean (standard error)
    23 ± 7.94
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Passive Joint Range of Motion (JROM) at Week 105

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    End point title
    Change From Baseline in Mean Passive Joint Range of Motion (JROM) at Week 105
    End point description
    Change was calculated as Week 105 minus baseline. Global JROM (% normal range of motion) is the average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive range of motion in Shoulder (Flexion/Extension, Abduction, Internal/External Rotation), Elbow (Flexion/Extension), Wrist (Flexion/Extension), Index Finger (Flexion/Extension [Combined Metacarpophalangeal joint (MCP), Proximal interphalangeal joint (PIP), Distal interphalangeal joint (DIP) motion]), Hip (Flexion/Extension, Abduction, Internal/External Rotation), Knee (Flexion/Extension), and Ankle (Dorsiflexion) divided by the normal range (American Academy of Orthopedic Surgeons and American Medical Association). All subjects for whom passive JROM were recorded at baseline and at Week 105.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 105
    End point values
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Number of subjects analysed
    84
    Units: percentage
        arithmetic mean (standard error)
    0.63 ± 0.64
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Combined Liver and Spleen Volume at Week 105

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    End point title
    Change From Baseline in Mean Combined Liver and Spleen Volume at Week 105
    End point description
    Determined by Magnetic Resonance Imaging (MRI). The change was calculated as Week 105 minus baseline. All subjects for whom combined liver and spleen volume were recorded at baseline and at Week 105.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 105
    End point values
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Number of subjects analysed
    79
    Units: cubic centimeters
        arithmetic mean (standard error)
    -325.5 ± 36.84
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Normalized Urine Glycosaminoglycans (GAG) Levels at Week 105

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    End point title
    Change From Baseline in Mean Normalized Urine Glycosaminoglycans (GAG) Levels at Week 105
    End point description
    Determined by urine testing. The change was calculated as Week 105 minus baseline. All subjects for whom normalized urine GAG levels were recorded at baseline and at Week 105.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 105
    End point values
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Number of subjects analysed
    87
    Units: µg GAG/mg creatinine
        arithmetic mean (standard error)
    -238.25 ± 13.333
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 105

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    End point title
    Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 105
    End point description
    Determined by echocardiogram. LVMI indexed to body surface area (g/m^2). The change was calculated as Week 105 minus baseline. All subjects for whom cardiac LVMI were recorded at baseline and at Week 105.
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 105
    End point values
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Number of subjects analysed
    71
    Units: g/m^2
        arithmetic mean (standard error)
    3.28 ± 3.826
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed throughout the duration of the TKT024EXT study. Adverse events were monitored from the time the first subject signed the informed consent until approximately 30 days after the last study visit.
    Adverse event reporting additional description
    The "Serious Adverse Events" table lists all serious adverse events that occurred during the study regardless of a relationship to the study drug. The "Other Adverse Events" table lists those non-serious adverse events that were determined to be possibly related to the study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    5.1
    Reporting groups
    Reporting group title
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Reporting group description
    Idursulfase 0.5 mg/kg administered by IV infusion once-weekly.

    Serious adverse events
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 94 (40.43%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neurilemmoma
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Poor venous access
         subjects affected / exposed
    10 / 94 (10.64%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Catheter related complication
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hernia nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma aggravated
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foreign body aspiration
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Obstructive airways disorder nos
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Tracheal stenosis
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Psychosomatic disease
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Airway complication of anaesthesia
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression nos
         subjects affected / exposed
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Tympanic membrane disorder nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain nos
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal hernia nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia nos
         subjects affected / exposed
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Acquired claw toe
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint contracture
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain in foot
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumonia nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocarditis bacterial nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobar pneumonia nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media chronic nos
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Otitis media serous nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media serous chronic nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia nos
         subjects affected / exposed
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection nos
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Idursulfase (0.5 mg/kg, IV, Once-weekly)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    94 / 94 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    32
    Pallor
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    8
    Hypotension nos
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    7
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    19
    Catheter site pain
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Fall
         subjects affected / exposed
    12 / 94 (12.77%)
         occurrences all number
    19
    Fatigue
         subjects affected / exposed
    12 / 94 (12.77%)
         occurrences all number
    22
    Influenza like illness
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    33
    Gait abnormal
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    8
    Injection site extravasation
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    8
    Malaise
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    12
    Pain nos
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    16
    Pyrexia
         subjects affected / exposed
    57 / 94 (60.64%)
         occurrences all number
    187
    Rigors
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    17
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Bronchitis nos
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    7
    Asthma nos
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    7
    Bronchospasm nos
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    19
    Cough
         subjects affected / exposed
    53 / 94 (56.38%)
         occurrences all number
    155
    Dyspnoea nos
         subjects affected / exposed
    14 / 94 (14.89%)
         occurrences all number
    24
    Nasal congestion
         subjects affected / exposed
    38 / 94 (40.43%)
         occurrences all number
    100
    Epistaxis
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    23
    Pharyngitis
         subjects affected / exposed
    46 / 94 (48.94%)
         occurrences all number
    102
    Nasopharyngitis
         subjects affected / exposed
    39 / 94 (41.49%)
         occurrences all number
    84
    Rhinitis allergic nos
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Productive cough
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    11
    Rhinorrhoea
         subjects affected / exposed
    31 / 94 (32.98%)
         occurrences all number
    70
    Rhinitis nos
         subjects affected / exposed
    14 / 94 (14.89%)
         occurrences all number
    20
    Rhonchi
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Sneezing
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    7
    Wheezing
         subjects affected / exposed
    15 / 94 (15.96%)
         occurrences all number
    28
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    8
    White blood cell count decreased
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    11
    Abrasion nos
         subjects affected / exposed
    17 / 94 (18.09%)
         occurrences all number
    24
    Limb injury nos
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Head injury
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    9
    Post procedural pain
         subjects affected / exposed
    15 / 94 (15.96%)
         occurrences all number
    25
    Thermal burn
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    9
    Dilatation atrial
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Tachycardia nos
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    24
    Ventricular hypertrophy
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 94 (19.15%)
         occurrences all number
    27
    Carpal tunnel syndrome
         subjects affected / exposed
    19 / 94 (20.21%)
         occurrences all number
    20
    Headache
         subjects affected / exposed
    53 / 94 (56.38%)
         occurrences all number
    296
    Hypoaesthesia
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    11
    Insomnia
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Migraine nos
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Anaemia nos
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    13 / 94 (13.83%)
         occurrences all number
    17
    Ear pain
         subjects affected / exposed
    24 / 94 (25.53%)
         occurrences all number
    34
    Ear haemorrhage
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Otorrhoea
         subjects affected / exposed
    27 / 94 (28.72%)
         occurrences all number
    88
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Visual acuity reduced
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Gastrointestinal disorders
    Abdominal pain nos
         subjects affected / exposed
    34 / 94 (36.17%)
         occurrences all number
    73
    Constipation
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    15
    Diarrhoea nos
         subjects affected / exposed
    32 / 94 (34.04%)
         occurrences all number
    78
    Dyspepsia
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    19
    Flatulence
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Gastroenteritis nos
         subjects affected / exposed
    10 / 94 (10.64%)
         occurrences all number
    12
    Loose stools
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    24 / 94 (25.53%)
         occurrences all number
    44
    Toothache
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Umbilical hernia nos
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Vomiting nos
         subjects affected / exposed
    39 / 94 (41.49%)
         occurrences all number
    102
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Acne nos
         subjects affected / exposed
    14 / 94 (14.89%)
         occurrences all number
    17
    Eczema
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Contusion
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    10
    Erythema
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    35
    Rash macular
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    11
    Pruritus
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    27
    Rash nos
         subjects affected / exposed
    20 / 94 (21.28%)
         occurrences all number
    60
    Rash papular
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    8
    Skin lesion nos
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    13
    Rash pruritic
         subjects affected / exposed
    10 / 94 (10.64%)
         occurrences all number
    16
    Urticaria nos
         subjects affected / exposed
    14 / 94 (14.89%)
         occurrences all number
    54
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    39 / 94 (41.49%)
         occurrences all number
    81
    Back pain
         subjects affected / exposed
    23 / 94 (24.47%)
         occurrences all number
    39
    Musculoskeletal stiffness
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    13
    Neck pain
         subjects affected / exposed
    17 / 94 (18.09%)
         occurrences all number
    24
    Pain in foot
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    7
    Pain in limb
         subjects affected / exposed
    29 / 94 (30.85%)
         occurrences all number
    59
    Infections and infestations
    Ear infection nos
         subjects affected / exposed
    36 / 94 (38.30%)
         occurrences all number
    91
    Furuncle
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Influenza
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    11
    Localised infection
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Lower respiratory tract infection nos
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    11
    Otitis media nos
         subjects affected / exposed
    22 / 94 (23.40%)
         occurrences all number
    37
    Otitis media serous nos
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Pneumonia nos
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Respiratory tract infection nos
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    12
    Sinusitis nos
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    16
    Tinea pedis
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    21
    Skin fungal infection nos
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    9
    Tonsillitis
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    6
    Upper respiratory tract infection nos
         subjects affected / exposed
    47 / 94 (50.00%)
         occurrences all number
    106
    Tooth caries nos
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    8
    Upper respiratory tract infection viral nos
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    13
    Viral infection nos
         subjects affected / exposed
    10 / 94 (10.64%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2004
    Clarified the maintenance of the original blinded treatment assignments in the TKT024 study during the first year of the TKT024EXT study. This change was made to minimize potential bias in evaluation and testing of subjects during the first year of Study TKT024EXT.
    26 Jul 2006
    Changed the study Medical Monitor and the Sponsor's signatory and expanded the visit window for visit 1 from the Week 53 visit of protocol TKT024 to the first visit of protocol TKT024EXT in order to accommodate logistical challenges encountered during the transfer of subjects from main sites to local care sites.
    26 Jul 2006
    Amendment 2 was not processed at the clinical sites, all of these changes were included in amendment 3. Extended the protocol into a second study phase to allow continued treatment after the second year of the study until idursulfase became commercially available and revised safety information presented in the model informed consent based on updated information for Studies TKT024, TKT024EXT, and TKT018. The sponsor's name was changed from Transkaryotic Therapies, Inc. to Shire Human Genetic Therapies, Inc. (Shire HGT).

    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.
    This study design was open-label, and the lack of a concurrently followed placebo group limits the strength of the observations, because the progression of the disease is variable and has not been well described.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/17185020
    http://www.ncbi.nlm.nih.gov/pubmed/21150784
    http://www.ncbi.nlm.nih.gov/pubmed/16912578
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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