Mucopolysaccharidosis II
Conditions
Keywords
Mucopolysaccharidosis II, MPS II, Hunter Syndrome, iduronate-2-sulfatase, I2S, Iduronate-2-sulfatase deficiency
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.
Interventions
BIOLOGICALIduronate-2-sulfatase enzyme replacement therapy
Patients will receive weekly infusions of idursulfase at a dose of 0.5 mg/kg.
BIOLOGICALiduronate-2-sulfatase enzyme replacement therapy
Patients will receive every other week infusions of idursulfase at a dose of 0.5 mg/kg.
BIOLOGICALPlacebo
Patients will receive weekly infusions of placebo.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
5 Years to 25 Years
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 3. 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). 4. Must be male, 5 to 25 years of age. 5. Forced vital capacity of \<80% of predicted obtained at the baseline evaluation of this study. 6. Must be able to adequately perform the testing required in this study, including reproducible pulmonary function testing by spirometry, as judged by the investigator. 7. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Mean Combined Liver and Spleen Volume at Baseline | 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 | Baseline, 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 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). |
| 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. |
| 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. |
| 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). |
Countries
Brazil, Germany, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Idursulfase Weekly (0.5 mg/kg) Idursulfase 0.5 mg/kg administered once-weekly by intravenous infusion for one year (52 infusions). | 32 |
| Idursulfase EOW (0.5 mg/kg) 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). | 32 |
| Placebo Placebo matching to idursulfase administered once-weekly by intravenous infusion for one year (52 infusions). | 32 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Idursulfase Weekly (0.5 mg/kg) | Idursulfase EOW (0.5 mg/kg) | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 15.14 years STANDARD_DEVIATION 6.293 | 14.40 years STANDARD_DEVIATION 7.019 | 13.12 years STANDARD_DEVIATION 6.908 | 14.22 years STANDARD_DEVIATION 6.729 |
| Age, Customized 12 to 18 years | 10 Participants | 9 Participants | 10 Participants | 29 Participants |
| Age, Customized 19 to 25 years | 7 Participants | 7 Participants | 5 Participants | 19 Participants |
| Age, Customized 5 to 11 years | 14 Participants | 14 Participants | 15 Participants | 43 Participants |
| Age, Customized greater than equal to (>=) 26 years | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Europe | 14 Participants | 14 Participants | 13 Participants | 41 Participants |
| Region of Enrollment North America | 11 Participants | 11 Participants | 12 Participants | 34 Participants |
| Region of Enrollment South America | 7 Participants | 7 Participants | 7 Participants | 21 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 32 Participants | 32 Participants | 32 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 32 / 32 | 32 / 32 |
| serious Total, serious adverse events | 9 / 32 | 8 / 32 | 9 / 32 |
Outcome results
Primary
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.
Time frame: Baseline, Week 53
Population: Intent-to-treat (ITT) population, Only participants receiving Idursulfase Weekly or Placebo were to be analyzed for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53 | 69.81 sum of the ranked scores | Standard Error 7.03 |
| Idursulfase EOW (0.5 mg/kg) | Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53 | 50.86 sum of the ranked scores | Standard Error 8.07 |
Comparison: p-value for treatment difference based on Analysis of covariance (ANCOVA) model containing treatment, region, baseline participant age, and baseline disease score.p-value: 0.004995% CI: [5.99, 31.93]ANCOVA
Secondary
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).
Time frame: Baseline, Week 53
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 | Baseline | 66.86 percentage of normal range of motion | Standard Error 1.85 |
| Idursulfase Weekly (0.5 mg/kg) | Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 | Change at Week 53 | 0.89 percentage of normal range of motion | Standard Error 0.87 |
| Idursulfase EOW (0.5 mg/kg) | Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 | Baseline | 67.36 percentage of normal range of motion | Standard Error 1.43 |
| Idursulfase EOW (0.5 mg/kg) | Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 | Change at Week 53 | -0.61 percentage of normal range of motion | Standard Error 0.94 |
| Placebo | Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 | Baseline | 67.70 percentage of normal range of motion | Standard Error 1.59 |
| Placebo | Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 | Change at Week 53 | 0.70 percentage of normal range of motion | Standard Error 1.1 |
Secondary
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).
Time frame: Baseline, Week 53
Population: ITT population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 | Baseline | 325.59 mcg GAG/mg creatinine | Standard Error 25.79 |
| Idursulfase Weekly (0.5 mg/kg) | Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 | Change at Week 53 | -189.23 mcg GAG/mg creatinine | Standard Error 25.76 |
| Idursulfase EOW (0.5 mg/kg) | Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 | Change at Week 53 | -154.98 mcg GAG/mg creatinine | Standard Error 17.18 |
| Idursulfase EOW (0.5 mg/kg) | Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 | Baseline | 338.08 mcg GAG/mg creatinine | Standard Error 21.03 |
| Placebo | Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 | Baseline | 419.40 mcg GAG/mg creatinine | Standard Error 34.37 |
| Placebo | Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 | Change at Week 53 | 18.16 mcg GAG/mg creatinine | Standard Error 29.94 |
Secondary
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.
Time frame: Baseline
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline | 105.18 gram per square meter (g/m^2) | Standard Error 6.86 |
| Idursulfase EOW (0.5 mg/kg) | Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline | 89.42 gram per square meter (g/m^2) | Standard Error 4.38 |
| Placebo | Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline | 95.55 gram per square meter (g/m^2) | Standard Error 5.96 |
Secondary
Mean Combined Liver and Spleen Volume at Baseline
Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).
Time frame: Baseline
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Mean Combined Liver and Spleen Volume at Baseline | 1578.48 milliliter (mL) | Standard Error 80.75 |
| Idursulfase EOW (0.5 mg/kg) | Mean Combined Liver and Spleen Volume at Baseline | 1442.2 milliliter (mL) | Standard Error 63.54 |
| Placebo | Mean Combined Liver and Spleen Volume at Baseline | 1485.28 milliliter (mL) | Standard Error 70.19 |
Secondary
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.
Time frame: Baseline, Week 53
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 | -1.34 percent change | Standard Error 5.05 |
| Idursulfase EOW (0.5 mg/kg) | Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 | 6.71 percent change | Standard Error 4.03 |
| Placebo | Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 | 3.56 percent change | Standard Error 4.12 |
Secondary
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.
Time frame: Baseline, Week 53
Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idursulfase Weekly (0.5 mg/kg) | Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 | -25.81 percent change | Standard Error 1.44 |
| Idursulfase EOW (0.5 mg/kg) | Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 | -23.73 percent change | Standard Error 1.49 |
| Placebo | Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 | 0.27 percent change | Standard Error 1.66 |