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Iduronate-2-sulfatase Enzyme Replacement Therapy in Mucopolysaccharidosis II (MPS II)

Sponsor
Shire (Industry)
Overall Status
Completed
CT.gov ID
NCT00069641
Collaborator
(none)
96
Enrollment
9
Locations
3
Arms
17.9
Actual Duration (Months)
10.7
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether the administration of iduronate-2-sulfatase enzyme in a weekly or every other week therapy frequency is safe and efficacious in patients with MPS II.

Condition or Disease Intervention/Treatment Phase
  • Biological: Iduronate-2-sulfatase enzyme replacement therapy
  • Biological: iduronate-2-sulfatase enzyme replacement therapy
  • Biological: Placebo
 Phase 2/Phase 3

Detailed Description

MPS II is a rare, X-linked, lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2-sulfatase. Because of this deficiency, glycosaminoglycans (GAG) accumulate in multiple tissues and organs, resulting in progressive cellular and organ system dysfunction. The purpose of this study is to determine if one year of therapy with iduronate-2-sulfatase enzyme replacement therapy, at a dose of 0.5mg/kg, weekly or every other week, is safe, and results in clinically meaningful improvement in multiple organ function, compared with a placebo group. Upon completion of the study, patients will be eligible to enroll in an open-label maintenance study.

Study Design

Study Type:
Interventional
Actual Enrollment :
96 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Weekly and Every Other Week Dosing Regimens of Iduronate-2-Sulfatase Enzyme Replacement Therapy in Patients With MPS II
Actual Study Start Date :
Sep 18, 2003
Actual Primary Completion Date :
Mar 16, 2005
Actual Study Completion Date :
Mar 16, 2005

Arms and Interventions

Arm Intervention/Treatment
Experimental: Idursulfase weekly (0.5 mg/kg)

Biological: Iduronate-2-sulfatase enzyme replacement therapy
Patients will receive weekly infusions of idursulfase at a dose of 0.5 mg/kg.
Other Names:
  • Elaprase

    		•
    Experimental: Idursulfase every other week (0.5 mg/kg)

    Biological: iduronate-2-sulfatase enzyme replacement therapy
    Patients will receive every other week infusions of idursulfase at a dose of 0.5 mg/kg.
    Other Names:
  • Elaprase

    		•
    Placebo Comparator: Placebo

    Biological: Placebo
    Patients will receive weekly infusions of placebo.

    Outcome Measures

    Primary Outcome Measures

    1. Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53 [Baseline, Week 53]

      The 2-component composite variable consists of the sum of the ranked changes from baseline to Week 53 for percent predicted Forced Vital Capacity (FVC) and 6-Minute Walking Test (6MWT) total distance walked. For the 2 treatment groups being compared, ranking occurred within the comparison treatment groups combined (idursulfase weekly and placebo treatment groups). These comparison groups were pooled and ranked for each component separately. Within each component (% predicted FVC, 6MWT), the change from baseline was then ranked. The lowest change value was assigned a rank of 1, the next lowest a rank of 2, etc. The composite score for each participant was the sum of the 2 ranked scores corresponding to the 2 individual components (% predicted FVC and 6MWT) for each participant. Thus, the greater the composite score (greater the sum of the ranks of the changes from baseline, where the lowest change was ranked as 1), the greater the improvement.

    Secondary Outcome Measures

    1. Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 [Baseline, Week 53]

      Change was calculated at Week 53 from baseline. Global JROM (% of 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).

    2. Mean Combined Liver and Spleen Volume at Baseline [Baseline]

      Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).

    3. Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 [Baseline, Week 53]

      Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI). Change was calculated at Week 53 from baseline.

    4. Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 [Baseline, Week 53]

      Mean normalized urine GAG was analyzed using urine testing. Change was calculated at Week 53 from baseline. The urine GAG levels were normalized to urine creatinine and were reported as microgram GAG per milligram creatinine (mcg GAG/mg creatinine).

    5. Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline [Baseline]

      Cardiac LVMI was determined by echocardiography. LVMI is the left ventricular mass (LVM, in grams [g]) indexed to body surface area (BSA), in square meter [m^2]. LVMI (in gram per square meter [g/m^2]) = LVM divided by BSA.

    6. Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 [Baseline, Week 53]

      Cardiac LVMI was determined by echocardiography. Change was calculated at Week 53 from baseline. LVMI is the LVM, in grams indexed to BSA, in square meter [m^2]. LVMI in g/m^2 = LVM divided by BSA.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    5 Years to 25 Years
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    To be eligible to participate in this study, patients must meet the following inclusion criteria prior to enrollment:

    1. The diagnosis of MPS II will be determined by the investigator based upon both clinical and biochemical criteria.

    2. All patients must have at least one of the following Clinical Criteria considered by the investigator to be MPS II-related:

    • Hepatosplenomegaly

    • Radiographic evidence of dysostosis multiplex

    • Valvular heart disease

    • Evidence of obstructive pulmonary disease

    1. In addition, patients must have the following Biochemical Criteria:

    • Documented deficiency in iduronate-2-sulfastase enzyme activity of less than or equal to 10% of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).

    • A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).

    1. Must be male, 5 to 25 years of age.

    2. Forced vital capacity of <80% of predicted obtained at the baseline evaluation of this study.

    3. Must be able to adequately perform the testing required in this study, including reproducible pulmonary function testing by spirometry, as judged by the investigator.

    4. Patient, patient's parent(s), or legally authorized guardian must have voluntarily signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient.

    Exclusion Criteria:

    Patients meeting any of the following criteria are not eligible for participation in this study:

    1. Patient has received treatment with another investigational therapy within the past 60 days.

    2. Patient, patient's parent(s), or patient's legal guardian is unable to understand the nature, scope, and possible consequences of the study.

    3. Patient is unable to comply with the protocol (e.g., due to a medical condition such as cervical cord compression or uncooperative attitude) or is unlikely to complete the study, as determined by the investigator.

    4. Patient has a tracheostomy.

    5. Patient has received a bone marrow or cord blood transplant.

    6. Patient with known hypersensitivity to any of the components of iduronate-2-sulfatase.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital Oakland Oakland California United States 94609
    2 St. Louis Children's Hospital, Washington University Saint Louis Missouri United States 63110
    3 University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27599
    4 Texas Children's Hospital, Baylor College of Medicine Houston Texas United States 77030
    5 Hospital de Clinicas de Porto Alegre Porto Alegre Brazil
    6 Children's Hospital, Johannes-Gutenburg Universitaet Mainz Mainz Germany
    7 Addenbrooke's Hospital Cambridge England United Kingdom CB2 2QQ
    8 Great Ormond Street Hospital for Sick Children London England United Kingdom WC1N3JH
    9 Royal Manchester Children's Hospital Manchester England United Kingdom M27 4HA

    Sponsors and Collaborators

    • Shire

    Investigators

    • Study Director: Study Director, Takeda

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Shire
    ClinicalTrials.gov Identifier:
    NCT00069641
    Other Study ID Numbers:
    • TKT024
    First Posted:
    Oct 1, 2003
    Last Update Posted:
    Jun 10, 2021
    Last Verified:
    May 1, 2021
    Keywords provided by Shire
    Mucopolysaccharidosis II
    MPS II
    Hunter Syndrome
    iduronate-2-sulfatase
    I2S
    Iduronate-2-sulfatase deficiency
    Additional relevant MeSH terms:
    Mucopolysaccharidosis II
    Mucopolysaccharidoses

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase Every Other Week (EOW) (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 milligram per kilogram (mg/kg) administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Period Title: Overall Study
    STARTED 32 32 32
    COMPLETED 31 32 31
    NOT COMPLETED 1 0 1

    Baseline Characteristics

    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo Total
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions). Total of all reporting groups
    Overall Participants 32 32 32 96
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    15.14
    (6.293)
    14.40
    (7.019)
    13.12
    (6.908)
    14.22
    (6.729)
    Age, Customized (Count of Participants)
    5 to 11 years
    14
    43.8%
    14
    43.8%
    15
    46.9%
    43
    44.8%
    12 to 18 years
    10
    31.3%
    9
    28.1%
    10
    31.3%
    29
    30.2%
    19 to 25 years
    7
    21.9%
    7
    21.9%
    5
    15.6%
    19
    19.8%
    greater than equal to (>=) 26 years
    1
    3.1%
    2
    6.3%
    2
    6.3%
    5
    5.2%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Male
    32
    100%
    32
    100%
    32
    100%
    96
    100%
    Region of Enrollment (Count of Participants)
    North America
    11
    34.4%
    11
    34.4%
    12
    37.5%
    34
    35.4%
    South America
    7
    21.9%
    7
    21.9%
    7
    21.9%
    21
    21.9%
    Europe
    14
    43.8%
    14
    43.8%
    13
    40.6%
    41
    42.7%

    Outcome Measures

    1. Secondary Outcome
    Title Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53
    Description Change was calculated at Week 53 from baseline. Global JROM (% of 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).
    Time Frame Baseline, Week 53

    Outcome Measure Data

    Analysis Population Description
    ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 31 32 31
    Baseline
    66.86
    (1.85)
    67.36
    (1.43)
    67.70
    (1.59)
    Change at Week 53
    0.89
    (0.87)
    -0.61
    (0.94)
    0.70
    (1.10)
    2. Secondary Outcome
    Title Mean Combined Liver and Spleen Volume at Baseline
    Description Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 31 29 30
    Mean (Standard Error) [milliliter (mL)]
    1578.48
    (80.75)
    1442.2
    (63.54)
    1485.28
    (70.19)
    3. Secondary Outcome
    Title Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53
    Description Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI). Change was calculated at Week 53 from baseline.
    Time Frame Baseline, Week 53

    Outcome Measure Data

    Analysis Population Description
    ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 31 29 30
    Mean (Standard Error) [percent change]
    -25.81
    (1.44)
    -23.73
    (1.49)
    0.27
    (1.66)
    4. Secondary Outcome
    Title Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53
    Description Mean normalized urine GAG was analyzed using urine testing. Change was calculated at Week 53 from baseline. The urine GAG levels were normalized to urine creatinine and were reported as microgram GAG per milligram creatinine (mcg GAG/mg creatinine).
    Time Frame Baseline, Week 53

    Outcome Measure Data

    Analysis Population Description
    ITT population.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 32 32 32
    Baseline
    325.59
    (25.79)
    338.08
    (21.03)
    419.40
    (34.37)
    Change at Week 53
    -189.23
    (25.76)
    -154.98
    (17.18)
    18.16
    (29.94)
    5. Primary Outcome
    Title Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53
    Description The 2-component composite variable consists of the sum of the ranked changes from baseline to Week 53 for percent predicted Forced Vital Capacity (FVC) and 6-Minute Walking Test (6MWT) total distance walked. For the 2 treatment groups being compared, ranking occurred within the comparison treatment groups combined (idursulfase weekly and placebo treatment groups). These comparison groups were pooled and ranked for each component separately. Within each component (% predicted FVC, 6MWT), the change from baseline was then ranked. The lowest change value was assigned a rank of 1, the next lowest a rank of 2, etc. The composite score for each participant was the sum of the 2 ranked scores corresponding to the 2 individual components (% predicted FVC and 6MWT) for each participant. Thus, the greater the composite score (greater the sum of the ranks of the changes from baseline, where the lowest change was ranked as 1), the greater the improvement.
    Time Frame Baseline, Week 53

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population, Only participants receiving "Idursulfase Weekly" or "Placebo" were to be analyzed for this outcome.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 32 32
    Mean (Standard Error) [sum of the ranked scores]
    69.81
    (7.03)
    50.86
    (8.07)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Idursulfase Weekly (0.5 mg/kg), Idursulfase EOW (0.5 mg/kg)
    Comments p-value for treatment difference based on Analysis of covariance (ANCOVA) model containing treatment, region, baseline participant age, and baseline disease score.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0049
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 18.96
    Confidence Interval (2-Sided) 95%
    5.99 to 31.93
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.47
    Estimation Comments
    6. Secondary Outcome
    Title Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline
    Description Cardiac LVMI was determined by echocardiography. LVMI is the left ventricular mass (LVM, in grams [g]) indexed to body surface area (BSA), in square meter [m^2]. LVMI (in gram per square meter [g/m^2]) = LVM divided by BSA.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 31 31 31
    Mean (Standard Error) [gram per square meter (g/m^2)]
    105.18
    (6.86)
    89.42
    (4.38)
    95.55
    (5.96)
    7. Secondary Outcome
    Title Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53
    Description Cardiac LVMI was determined by echocardiography. Change was calculated at Week 53 from baseline. LVMI is the LVM, in grams indexed to BSA, in square meter [m^2]. LVMI in g/m^2 = LVM divided by BSA.
    Time Frame Baseline, Week 53

    Outcome Measure Data

    Analysis Population Description
    ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    Measure Participants 31 31 31
    Mean (Standard Error) [percent change]
    -1.34
    (5.05)
    6.71
    (4.03)
    3.56
    (4.12)

    Adverse Events

    Time Frame 52 weeks
    Adverse Event Reporting Description
    Arm/Group Title Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Arm/Group Description Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). Idursulfase 0.5 mg/kg administered every other week by intravenous infusion for one year (26 infusions) along with placebo matching to idursulfase every other week (alternating with idursulfase) by intravenous infusion for one year (26 infusions). Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions).
    All Cause Mortality
    Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/32 (28.1%) 8/32 (25%) 9/32 (28.1%)
    Cardiac disorders
    Aortic valve incompetence 1/32 (3.1%) 1 0/32 (0%) 0 1/32 (3.1%) 1
    Arrhythmia not otherwise specified (nos) 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Atrial tachycardia 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Cyanosis nos 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Heart valve insufficiency 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Ear and labyrinth disorders
    Ear disorder nos 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Hearing impaired 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Otorrhoea 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Gastrointestinal disorders
    Appendicitis 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Nausea 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Pancreatitis acute 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Umbilical hernia nos 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    General disorders
    Hernia nos 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Pyrexia 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Infections and infestations
    Bronchopneumonia nos 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Localised infection 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Otitis media chronic nos 0/32 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2
    Otitis media serous nos 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Pilonidal sinus infected 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Pneumonia streptococcal 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Tooth caries nos 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Wound infection due to staphylococcus aureus 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Injury, poisoning and procedural complications
    Anaesthesia intubation complication 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Medical device complication 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Investigations
    Blood carbon dioxide increased 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Nervous system disorders
    Carpal tunnel syndrome 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Headache 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Psychiatric disorders
    Adjustment disorder with depressed mood 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Phobia 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Bronchospasm nos 1/32 (3.1%) 1 0/32 (0%) 0 1/32 (3.1%) 1
    Epistaxis 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Pulmonary embolism 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Respiratory failure 1/32 (3.1%) 1 0/32 (0%) 0 0/32 (0%) 0
    Tonsillar hypertrophy 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Skin and subcutaneous tissue disorders
    Rash nos 0/32 (0%) 0 0/32 (0%) 0 1/32 (3.1%) 1
    Vascular disorders
    Orthostatic hypotension 0/32 (0%) 0 1/32 (3.1%) 1 0/32 (0%) 0
    Poor venous access 2/32 (6.3%) 2 3/32 (9.4%) 4 2/32 (6.3%) 2
    Other (Not Including Serious) Adverse Events
    Idursulfase Weekly (0.5 mg/kg) Idursulfase EOW (0.5 mg/kg) Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 32/32 (100%) 32/32 (100%) 32/32 (100%)
    Blood and lymphatic system disorders
    Lymphadenopathy 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Cardiac disorders
    Atrial hypertrophy 2/32 (6.3%) 2 0/32 (0%) 0 3/32 (9.4%) 3
    Tachycardia nos 1/32 (3.1%) 1 3/32 (9.4%) 5 2/32 (6.3%) 10
    Ventricular hypertrophy 2/32 (6.3%) 2 2/32 (6.3%) 2 1/32 (3.1%) 1
    Ear and labyrinth disorders
    Cerumen impaction 0/32 (0%) 0 2/32 (6.3%) 2 2/32 (6.3%) 2
    Deafness nos 1/32 (3.1%) 1 0/32 (0%) 0 2/32 (6.3%) 2
    Deafness unilateral 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Ear disorder nos 2/32 (6.3%) 3 1/32 (3.1%) 1 0/32 (0%) 0
    Ear haemorrhage 0/32 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 3
    Ear pain 7/32 (21.9%) 7 5/32 (15.6%) 9 6/32 (18.8%) 13
    Eustachian tube dysfunction 1/32 (3.1%) 1 2/32 (6.3%) 5 0/32 (0%) 0
    Hypoacusis 1/32 (3.1%) 1 5/32 (15.6%) 5 4/32 (12.5%) 5
    Otorrhoea 7/32 (21.9%) 20 7/32 (21.9%) 17 9/32 (28.1%) 21
    Sensation of block in ear 0/32 (0%) 0 3/32 (9.4%) 3 1/32 (3.1%) 1
    Tympanic membrane perforation 0/32 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2
    Eye disorders
    Conjunctivitis 1/32 (3.1%) 1 0/32 (0%) 0 3/32 (9.4%) 3
    Conjunctivitis allergic 2/32 (6.3%) 2 1/32 (3.1%) 1 0/32 (0%) 0
    Eye pain 3/32 (9.4%) 3 1/32 (3.1%) 1 1/32 (3.1%) 1
    Hypermetropia 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Lacrimation increased 3/32 (9.4%) 6 0/32 (0%) 0 1/32 (3.1%) 2
    Myopia 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Vision blurred 3/32 (9.4%) 5 0/32 (0%) 0 2/32 (6.3%) 2
    Gastrointestinal disorders
    Abdominal discomfort 0/32 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1
    Abdominal pain nos 11/32 (34.4%) 24 17/32 (53.1%) 36 11/32 (34.4%) 20
    Abdominal pain upper 5/32 (15.6%) 14 2/32 (6.3%) 2 2/32 (6.3%) 3
    Constipation 2/32 (6.3%) 4 1/32 (3.1%) 1 1/32 (3.1%) 2
    Diarrhoea nos 11/32 (34.4%) 22 12/32 (37.5%) 24 15/32 (46.9%) 29
    Dyspepsia 4/32 (12.5%) 5 4/32 (12.5%) 18 0/32 (0%) 0
    Flatulence 0/32 (0%) 0 2/32 (6.3%) 13 1/32 (3.1%) 1
    Gastroenteritis nos 1/32 (3.1%) 1 3/32 (9.4%) 4 3/32 (9.4%) 3
    Gastrooesophageal reflux disease 1/32 (3.1%) 1 2/32 (6.3%) 2 0/32 (0%) 0
    Inguinal hernia nos 0/32 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2
    Loose stools 1/32 (3.1%) 1 0/32 (0%) 0 2/32 (6.3%) 4
    Nausea 7/32 (21.9%) 18 9/32 (28.1%) 16 9/32 (28.1%) 17
    Swollen tongue 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Toothache 2/32 (6.3%) 2 0/32 (0%) 0 2/32 (6.3%) 2
    Umbilical hernia nos 0/32 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1
    Vomiting nos 8/32 (25%) 22 18/32 (56.3%) 37 16/32 (50%) 43
    General disorders
    Asthenia 3/32 (9.4%) 3 1/32 (3.1%) 1 0/32 (0%) 0
    Catheter site pain 0/32 (0%) 0 2/32 (6.3%) 3 3/32 (9.4%) 3
    Chest pain 3/32 (9.4%) 7 2/32 (6.3%) 2 0/32 (0%) 0
    Fall 0/32 (0%) 0 4/32 (12.5%) 7 4/32 (12.5%) 10
    Fatigue 2/32 (6.3%) 2 4/32 (12.5%) 10 3/32 (9.4%) 5
    Gait abnormal 0/32 (0%) 0 1/32 (3.1%) 1 2/32 (6.3%) 2
    Hernia pain 1/32 (3.1%) 1 2/32 (6.3%) 3 1/32 (3.1%) 2
    Inflammation localised 2/32 (6.3%) 3 0/32 (0%) 0 1/32 (3.1%) 1
    Influenza like illness 3/32 (9.4%) 7 8/32 (25%) 12 4/32 (12.5%) 6
    Infusion site pain 3/32 (9.4%) 5 3/32 (9.4%) 3 2/32 (6.3%) 2
    Infusion site swelling 4/32 (12.5%) 6 4/32 (12.5%) 4 1/32 (3.1%) 1
    Injection site bruising 0/32 (0%) 0 2/32 (6.3%) 3 0/32 (0%) 0
    Injection site extravasation 2/32 (6.3%) 2 2/32 (6.3%) 3 2/32 (6.3%) 3
    Injection site haemorrhage 1/32 (3.1%) 1 0/32 (0%) 0 2/32 (6.3%) 2
    Lethargy 2/32 (6.3%) 4 0/32 (0%) 0 0/32 (0%) 0
    Malaise 5/32 (15.6%) 7 1/32 (3.1%) 1 3/32 (9.4%) 3
    Oedema peripheral 2/32 (6.3%) 11 0/32 (0%) 0 1/32 (3.1%) 1
    Pain nos 1/32 (3.1%) 1 1/32 (3.1%) 1 2/32 (6.3%) 2
    Pyrexia 20/32 (62.5%) 83 18/32 (56.3%) 68 19/32 (59.4%) 63
    Rigors 1/32 (3.1%) 1 3/32 (9.4%) 8 1/32 (3.1%) 1
    Sensation of foreign body nos 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Infections and infestations
    Ear infection nos 8/32 (25%) 15 9/32 (28.1%) 17 9/32 (28.1%) 19
    Furuncle 1/32 (3.1%) 1 2/32 (6.3%) 3 1/32 (3.1%) 1
    Herpes simplex 2/32 (6.3%) 2 1/32 (3.1%) 4 0/32 (0%) 0
    Hordeolum 0/32 (0%) 0 2/32 (6.3%) 2 3/32 (9.4%) 3
    Influenza 2/32 (6.3%) 2 1/32 (3.1%) 1 1/32 (3.1%) 2
    Lice infestation 2/32 (6.3%) 2 0/32 (0%) 0 2/32 (6.3%) 2
    Localised infection 0/32 (0%) 0 3/32 (9.4%) 3 0/32 (0%) 0
    Lower respiratory tract infection nos 0/32 (0%) 0 2/32 (6.3%) 2 1/32 (3.1%) 1
    Otitis media nos 6/32 (18.8%) 8 7/32 (21.9%) 11 7/32 (21.9%) 9
    Otitis media serous nos 4/32 (12.5%) 8 2/32 (6.3%) 7 4/32 (12.5%) 6
    Respiratory tract infection nos 1/32 (3.1%) 1 2/32 (6.3%) 2 1/32 (3.1%) 1
    Sinusitis nos 5/32 (15.6%) 5 2/32 (6.3%) 5 3/32 (9.4%) 4
    Tonsillitis 2/32 (6.3%) 2 3/32 (9.4%) 3 1/32 (3.1%) 1
    Tracheobronchitis 1/32 (3.1%) 1 1/32 (3.1%) 1 3/32 (9.4%) 4
    Upper respiratory tract infection nos 12/32 (37.5%) 26 12/32 (37.5%) 34 10/32 (31.3%) 19
    Urinary tract infection nos 2/32 (6.3%) 3 0/32 (0%) 0 0/32 (0%) 0
    Varicella 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Viral infection nos 1/32 (3.1%) 1 1/32 (3.1%) 1 2/32 (6.3%) 2
    Injury, poisoning and procedural complications
    Abrasion nos 0/32 (0%) 0 3/32 (9.4%) 6 3/32 (9.4%) 6
    Arthropod bite 3/32 (9.4%) 5 1/32 (3.1%) 1 0/32 (0%) 0
    Head injury 0/32 (0%) 0 4/32 (12.5%) 5 1/32 (3.1%) 1
    Muscle strain 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Post procedural pain 2/32 (6.3%) 3 3/32 (9.4%) 5 3/32 (9.4%) 3
    Skin laceration 2/32 (6.3%) 2 3/32 (9.4%) 3 1/32 (3.1%) 1
    Investigations
    Alanine aminotransferase increased 0/32 (0%) 0 0/32 (0%) 0 4/32 (12.5%) 6
    Aspartate aminotransferase increased 0/32 (0%) 0 0/32 (0%) 0 3/32 (9.4%) 3
    Blood alkaline phosphatase nos increased 1/32 (3.1%) 1 2/32 (6.3%) 2 2/32 (6.3%) 2
    Blood lactate dehydrogenase increased 1/32 (3.1%) 1 2/32 (6.3%) 3 0/32 (0%) 0
    Blood triglycerides increased 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Electrocardiogram abnormal nos 1/32 (3.1%) 1 2/32 (6.3%) 2 0/32 (0%) 0
    Gamma-Glutamyltransferase increased 0/32 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 3
    Haematocrit decreased 0/32 (0%) 0 0/32 (0%) 0 2/32 (6.3%) 2
    Haemoglobin decreased 1/32 (3.1%) 1 0/32 (0%) 0 2/32 (6.3%) 2
    Metabolism and nutrition disorders
    Appetite decreased nos 1/32 (3.1%) 1 2/32 (6.3%) 2 1/32 (3.1%) 3
    Hypokalaemia 2/32 (6.3%) 2 0/32 (0%) 0 1/32 (3.1%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 10/32 (31.3%) 26 14/32 (43.8%) 28 9/32 (28.1%) 15
    Back pain 8/32 (25%) 10 11/32 (34.4%) 25 8/32 (25%) 11
    Bone pain 2/32 (6.3%) 2 1/32 (3.1%) 1 0/32 (0%) 0
    Chest wall pain 4/32 (12.5%) 4 0/32 (0%) 0 0/32 (0%) 0
    Groin pain 1/32 (3.1%) 1 2/32 (6.3%) 4 0/32 (0%) 0
    Muscle cramp 2/32 (6.3%) 3 3/32 (9.4%) 4 1/32 (3.1%) 1
    Musculoskeletal chest pain 1/32 (3.1%) 1 3/32 (9.4%) 3 0/32 (0%) 0
    Myalgia 3/32 (9.4%) 3 4/32 (12.5%) 8 3/32 (9.4%) 4
    Neck pain 3/32 (9.4%) 4 4/32 (12.5%) 4 3/32 (9.4%) 7
    Pain in foot 2/32 (6.3%) 2 1/32 (3.1%) 3 2/32 (6.3%) 2
    Pain in limb 9/32 (28.1%) 20 9/32 (28.1%) 18 10/32 (31.3%) 14
    Peripheral swelling 1/32 (3.1%) 1 4/32 (12.5%) 4 2/32 (6.3%) 3
    Nervous system disorders
    Carpal tunnel syndrome 2/32 (6.3%) 2 0/32 (0%) 0 1/32 (3.1%) 1
    Dizziness 4/32 (12.5%) 10 6/32 (18.8%) 9 8/32 (25%) 16
    Headache 19/32 (59.4%) 132 21/32 (65.6%) 118 14/32 (43.8%) 80
    Hyperreflexia 1/32 (3.1%) 1 2/32 (6.3%) 2 1/32 (3.1%) 1
    Hypoaesthesia 0/32 (0%) 0 1/32 (3.1%) 1 2/32 (6.3%) 2
    Insomnia 1/32 (3.1%) 1 3/32 (9.4%) 22 1/32 (3.1%) 3
    Migraine nos 2/32 (6.3%) 2 0/32 (0%) 0 1/32 (3.1%) 3
    Paraesthesia 2/32 (6.3%) 6 2/32 (6.3%) 2 1/32 (3.1%) 3
    Post-Traumatic headache 0/32 (0%) 0 2/32 (6.3%) 3 0/32 (0%) 0
    Somnolence 0/32 (0%) 0 3/32 (9.4%) 3 1/32 (3.1%) 1
    Tremor 2/32 (6.3%) 4 1/32 (3.1%) 1 1/32 (3.1%) 1
    Psychiatric disorders
    Abnormal behaviour nos 2/32 (6.3%) 2 0/32 (0%) 0 3/32 (9.4%) 3
    Anxiety 2/32 (6.3%) 4 4/32 (12.5%) 5 0/32 (0%) 0
    Depression 3/32 (9.4%) 3 2/32 (6.3%) 2 0/32 (0%) 0
    Renal and urinary disorders
    Haematuria 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Reproductive system and breast disorders
    Testicular pain 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Asthma nos 3/32 (9.4%) 4 1/32 (3.1%) 3 2/32 (6.3%) 4
    Bronchitis nos 1/32 (3.1%) 1 1/32 (3.1%) 1 2/32 (6.3%) 2
    Bronchospasm nos 3/32 (9.4%) 5 2/32 (6.3%) 5 4/32 (12.5%) 11
    Cough 16/32 (50%) 30 16/32 (50%) 38 19/32 (59.4%) 42
    Dyspnoea nos 4/32 (12.5%) 10 3/32 (9.4%) 3 9/32 (28.1%) 11
    Epistaxis 2/32 (6.3%) 2 1/32 (3.1%) 5 4/32 (12.5%) 5
    Hypoxia 1/32 (3.1%) 2 3/32 (9.4%) 4 1/32 (3.1%) 1
    Nasal congestion 12/32 (37.5%) 18 16/32 (50%) 39 12/32 (37.5%) 23
    Nasal passage irritation 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Nasopharyngitis 4/32 (12.5%) 5 8/32 (25%) 16 5/32 (15.6%) 15
    Obstructive airways disorder nos 2/32 (6.3%) 2 0/32 (0%) 0 0/32 (0%) 0
    Pharyngitis 13/32 (40.6%) 19 11/32 (34.4%) 23 10/32 (31.3%) 18
    Respiratory tract congestion 1/32 (3.1%) 1 2/32 (6.3%) 2 2/32 (6.3%) 3
    Rhinitis allergic nos 3/32 (9.4%) 7 3/32 (9.4%) 3 3/32 (9.4%) 6
    Rhinitis nos 4/32 (12.5%) 5 0/32 (0%) 0 4/32 (12.5%) 4
    Rhinorrhoea 9/32 (28.1%) 14 10/32 (31.3%) 19 9/32 (28.1%) 20
    Rhonchi 3/32 (9.4%) 3 4/32 (12.5%) 4 5/32 (15.6%) 9
    Sleep apnoea syndrome 2/32 (6.3%) 2 1/32 (3.1%) 1 1/32 (3.1%) 1
    Sneezing 3/32 (9.4%) 3 2/32 (6.3%) 2 3/32 (9.4%) 4
    Tachypnoea 2/32 (6.3%) 3 0/32 (0%) 0 2/32 (6.3%) 3
    Upper respiratory tract congestion 1/32 (3.1%) 1 1/32 (3.1%) 1 2/32 (6.3%) 4
    Wheezing 5/32 (15.6%) 6 5/32 (15.6%) 7 5/32 (15.6%) 8
    Skin and subcutaneous tissue disorders
    Acne nos 3/32 (9.4%) 3 2/32 (6.3%) 2 0/32 (0%) 0
    Contusion 2/32 (6.3%) 2 5/32 (15.6%) 6 2/32 (6.3%) 2
    Dyshidrosis 0/32 (0%) 0 2/32 (6.3%) 2 0/32 (0%) 0
    Eczema 2/32 (6.3%) 3 0/32 (0%) 0 1/32 (3.1%) 2
    Erythema 2/32 (6.3%) 12 1/32 (3.1%) 3 1/32 (3.1%) 1
    Pruritus 10/32 (31.3%) 19 6/32 (18.8%) 14 5/32 (15.6%) 10
    Rash macular 2/32 (6.3%) 2 0/32 (0%) 0 1/32 (3.1%) 1
    Rash nos 8/32 (25%) 14 11/32 (34.4%) 39 10/32 (31.3%) 29
    Rash pruritic 5/32 (15.6%) 9 5/32 (15.6%) 6 0/32 (0%) 0
    Sweating increased 2/32 (6.3%) 3 2/32 (6.3%) 2 3/32 (9.4%) 3
    Urticaria nos 5/32 (15.6%) 10 4/32 (12.5%) 9 0/32 (0%) 0
    Vascular disorders
    Flushing 5/32 (15.6%) 9 5/32 (15.6%) 9 6/32 (18.8%) 7
    Hypertension nos 8/32 (25%) 23 5/32 (15.6%) 7 7/32 (21.9%) 10
    Hypotension nos 3/32 (9.4%) 5 2/32 (6.3%) 4 4/32 (12.5%) 9

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Study Director
    Organization Shire
    Phone +1 866 842 5335
    Email ClinicalTransparency@shire.com
    Responsible Party:
    Shire
    ClinicalTrials.gov Identifier:
    NCT00069641
    Other Study ID Numbers:
    • TKT024
    First Posted:
    Oct 1, 2003
    Last Update Posted:
    Jun 10, 2021
    Last Verified:
    May 1, 2021