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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Mucopolysaccharidosis II

Intervention / Treatment
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* Biological: Iduronate-2-sulfatase enzyme replacement therapy
* Biological: iduronate-2-sulfatase enzyme replacement therapy
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible to participate in this study, patients must meet the following inclusion criteria prior to enrollment: The diagnosis of MPS II will be determined by the investigator based upon both clinical and biochemical criteria. 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 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). Must be male, 5 to 25 years of age. Forced vital capacity of <80% of predicted obtained at the baseline evaluation of this study. Must be able to adequately perform the testing required in this study, including reproducible pulmonary function testing by spirometry, as judged by the investigator. 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: Patient has received treatment with another investigational therapy within the past 60 days. Patient, patient's parent(s), or patient's legal guardian is unable to understand the nature, scope, and possible consequences of the study. 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. Patient has a tracheostomy. Patient has received a bone marrow or cord blood transplant. Patient with known hypersensitivity to any of the components of iduronate-2-sulfatase.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idursulfase weekly (0.5 mg/kg)<br> | Biological: Iduronate-2-sulfatase enzyme replacement therapy<br>* Patients will receive weekly infusions of idursulfase at a dose of 0.5 mg/kg.<br>* Other names: Elaprase;|
| Experimental: Idursulfase every other week (0.5 mg/kg)<br> | Biological: iduronate-2-sulfatase enzyme replacement therapy<br>* Patients will receive every other week infusions of idursulfase at a dose of 0.5 mg/kg.<br>* Other names: Elaprase;|
| Placebo Comparator: Placebo<br> | Biological: Placebo<br>* Patients will receive weekly infusions of placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to 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. | Baseline, Week 53 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at 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). | Baseline, Week 53 | 
| Mean Combined Liver and Spleen Volume at Baseline | Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI). | Baseline | 
| Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 | Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI). Change was calculated at Week 53 from baseline. | Baseline, Week 53 | 
| Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at 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). | Baseline, Week 53 | 
| Mean Cardiac Left Ventricular Mass Index (LVMI) at 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. | Baseline | 
| Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at 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. | Baseline, Week 53 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidosis II, MPS II, Hunter Syndrome, iduronate-2-sulfatase, I2S, Iduronate-2-sulfatase deficiency