Back to resultsIduronate-2-sulfatase Enzyme Replacement Therapy in Mucopolysaccharidosis II (MPS II)
Primary Purpose
Mucopolysaccharidosis II
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Iduronate-2-sulfatase enzyme replacement therapy
iduronate-2-sulfatase enzyme replacement therapy
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Mucopolysaccharidosis II focused on measuring Mucopolysaccharidosis II, MPS II, Hunter Syndrome, iduronate-2-sulfatase, I2S, Iduronate-2-sulfatase deficiency
Eligibility Criteria
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.
Sites / Locations
- Children's Hospital Oakland
- St. Louis Children's Hospital, Washington University
- University of North Carolina at Chapel Hill
- Texas Children's Hospital, Baylor College of Medicine
- Hospital de Clinicas de Porto Alegre
- Children's Hospital, Johannes-Gutenburg Universitaet Mainz
- Addenbrooke's Hospital
- Great Ormond Street Hospital for Sick Children
- Royal Manchester Children's Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Idursulfase weekly (0.5 mg/kg)
Idursulfase every other week (0.5 mg/kg)
Placebo
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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).
Mean Combined Liver and Spleen Volume at Baseline
Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).
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.
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).
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00069641
Brief Title
Iduronate-2-sulfatase Enzyme Replacement Therapy in Mucopolysaccharidosis II (MPS II)
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
September 18, 2003 (Actual)
Primary Completion Date
March 16, 2005 (Actual)
Study Completion Date
March 16, 2005 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shire
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mucopolysaccharidosis II
Keywords
Mucopolysaccharidosis II, MPS II, Hunter Syndrome, iduronate-2-sulfatase, I2S, Iduronate-2-sulfatase deficiency
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
96 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Idursulfase weekly (0.5 mg/kg)
Arm Type
Experimental
Arm Title
Idursulfase every other week (0.5 mg/kg)
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Biological
Intervention Name(s)
Iduronate-2-sulfatase enzyme replacement therapy
Other Intervention Name(s)
Elaprase
Intervention Description
Patients will receive weekly infusions of idursulfase at a dose of 0.5 mg/kg.
Intervention Type
Biological
Intervention Name(s)
iduronate-2-sulfatase enzyme replacement therapy
Other Intervention Name(s)
Elaprase
Intervention Description
Patients will receive every other week infusions of idursulfase at a dose of 0.5 mg/kg.
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Patients will receive weekly infusions of placebo.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
Title
Mean Combined Liver and Spleen Volume at Baseline
Description
Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).
Time Frame
Baseline
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
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
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
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
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
Children's Hospital Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
St. Louis Children's Hospital, Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Texas Children's Hospital, Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Hospital de Clinicas de Porto Alegre
City
Porto Alegre
Country
Brazil
Facility Name
Children's Hospital, Johannes-Gutenburg Universitaet Mainz
City
Mainz
Country
Germany
Facility Name
Addenbrooke's Hospital
City
Cambridge
State/Province
England
ZIP/Postal Code
CB2 2QQ
Country
United Kingdom
Facility Name
Great Ormond Street Hospital for Sick Children
City
London
State/Province
England
ZIP/Postal Code
WC1N3JH
Country
United Kingdom
Facility Name
Royal Manchester Children's Hospital
City
Manchester
State/Province
England
ZIP/Postal Code
M27 4HA
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
33874971
Citation
Tandon PK, Kakkis ED. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis. 2021 Apr 19;16(1):183. doi: 10.1186/s13023-021-01805-5.
Results Reference
derived
PubMed Identifier
23837440
Citation
Raluy-Callado M, Chen WH, Whiteman DA, Fang J, Wiklund I. The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life. Orphanet J Rare Dis. 2013 Jul 10;8:101. doi: 10.1186/1750-1172-8-101.
Results Reference
derived
Learn more about this trial
Iduronate-2-sulfatase Enzyme Replacement Therapy in Mucopolysaccharidosis II (MPS II)
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