Hurler-Scheie Syndrome, Hurlers Syndrome, Mucopolysaccharidosis I
Conditions
Brief summary
This study is being conducted to demonstrate the safety and clinical efficacy of Aldurazyme treatment in MPS I patients
Interventions
BIOLOGICALrhIDU (recombinant human-Alpha-L-Iduronidase)
Patients in the active treatment group received Aldurazyme intravenously at a dose of 100 units/kg (approximately 0.58mg/kg) administered intravenously over approximately 4 hours once weekly for 26 weeks.
BIOLOGICALPlacebo
Patients in the Placebo-control group were administered a solution of 100mM sodium phosphate , 150mM sodium chloride, and 0.001% polysorbate-80, adjusted to a pH of 5.8 administered intravenously over a time period of approximately 4 hours once weekly for 26 weeks.
Sponsors
BioMarin/Genzyme LLC
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The patient had a documented diagnosis of MPS I confirmed by measurable clinical signs and symptoms of MPS I and a fibroblast or leukocyte alpha-L-iduronidase enzyme activity level of less than 10% of the lower limit of the normal range of the measuring laboratory. * Female patients of childbearing potential had a negative pregnancy test (urine-beta-human chorionic gonadotropin (hCG)) at baseline (all female patients of childbearing potential and sexually mature male patients were advised to use a medically accepted method of contraception throughout the study). * The patient was capable of standing independently for 6 minutes and walking a minimum of 5 meters within 6 minutes. * The patient was capable of performing a reproducible FVC maneuver. * The patient had a baseline FVC value that was less than or equal to 80% of the patient's predicted normal FVC value based on polgar predicted values for standing height for children 5 through 7 years of age and the Hankinson predicted values for ages 8 and above.
Exclusion criteria
* The patient had undergone a tracheostomy. * The patient had previously undergone a bone marrow transplantation. * The patient was pregnant or lactating. * The patient has received an investigational drug within 30 days prior to study enrollment. * The patient had a medical condition, serious intercurrent illness, or other extenuating circumstance that could have significantly interfered with study compliance including all prescribing evaluations and follow-up activities. * The patient had a known hypersensitivity to rhIDU or to components of the active or placebo test solutions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Baseline to Week 26 | Percent Predicted Forced Vital Capacity (FVC): the maximal exhaled breathe volume following a maximal inhaled breath. Overall Change from Baseline to Week 26 in percent predicted FVC = (observed value)/(predicted value) \* 100%). A higher value indicates a greater response. |
| Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Baseline to Week 26 | Six Minute Walk Test (6MWT): Distance walked (measured in meters) in 6 minutes. A longer distance indicates a greater response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Baseline to week 26 | CHAQ/HAQ) = Patient questionnaire that measures the degree of disability on a scale of 0 (no disability) to 3 (maximal disability). A lower score indicates a greater response. |
| Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Baseline to Week 26 | Apnea/Hypopnea Index (AHI): Number of absent (apnea) and shallow (hypopnea) breaths per hour of sleep. Overall change from Baseline to Week 26 in AHI. A greater decrease in events indicates a greater response. |
| Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Baseline to Week 26 | Urinary Glycosaminoglycan (GAG) Levels: Concentration of GAG relative to creatinine in urine. A greater decrease in GAG level indicates a greater response. |
| Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Baseline to Week 26 | Active Joint Range of Motion (ROM): Shoulder Flexion Ability to maximally raise one's arm overhead without assistance. Shoulder range of motion (mean of left and right arms) measured in degrees (0-180) by goniometry. Greater degree of flexion indicates greater response. |
| Overall Percent Change From Baseline to Week 26 in Liver Volume | Baseline to Week 26 | Liver Organ Volume: Volume of liver measured by Magnetic Resonance Imaging (MRI). Greater decrease in volume indicates a greater response. |
Countries
Canada, Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients in the placebo-control group were administered a solution of 100 mM sodium phosphate, 150 mM sodium chloride, and 0.001% polysorbate-80, adjusted to a pH of 5.8 administered intravenously over approximately 4 hours once weekly for 26 weeks. | 23 |
| Aldurazyme Treatment Patients in the active treatment group received Aldurazyme intravenously at a dose of 100 Units/kg (approximately 0.58 mg/kg = labeled dose) administered intravenously over approximately 4 hours once weekly for 26 weeks. | 22 |
| Total | 45 |
Baseline characteristics
| Characteristic | Placebo | Total | Aldurazyme Treatment |
|---|---|---|---|
| Age, Continuous | 15.4 years STANDARD_DEVIATION 7.63 | 15.5 years STANDARD_DEVIATION 8.04 | 15.6 years STANDARD_DEVIATION 8.63 |
| Age, Customized 13 to less than or equal to 18 years | 8 participants | 11 participants | 3 participants |
| Age, Customized 19 to less than or equal to 65 years | 5 participants | 12 participants | 7 participants |
| Age, Customized less than or equal to 12 years | 10 participants | 22 participants | 12 participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 21 Participants | 37 Participants | 16 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Female | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 22 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 23 | 21 / 22 |
| serious Total, serious adverse events | 0 / 23 | 3 / 22 |
Outcome results
Primary
Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC)
Percent Predicted Forced Vital Capacity (FVC): the maximal exhaled breathe volume following a maximal inhaled breath. Overall Change from Baseline to Week 26 in percent predicted FVC = (observed value)/(predicted value) \* 100%). A higher value indicates a greater response.
Time frame: Baseline to Week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Baseline | 54.2 Percent predicted FVC | Standard Deviation 16 |
| Placebo | Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Week 26 | 51.5 Percent predicted FVC | Standard Deviation 13.13 |
| Placebo | Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Overall change from Baseline to Week 26 | -2.7 Percent predicted FVC | Standard Deviation 7.12 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Baseline | 48.4 Percent predicted FVC | Standard Deviation 14.85 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Week 26 | 50.2 Percent predicted FVC | Standard Deviation 17.1 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Percent Predicted Forced Vital Capacity (FVC) | Overall change from Baseline to Week 26 | 1.8 Percent predicted FVC | Standard Deviation 7.7 |
Primary
Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT)
Six Minute Walk Test (6MWT): Distance walked (measured in meters) in 6 minutes. A longer distance indicates a greater response.
Time frame: Baseline to Week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Baseline | 366.7 meters | Standard Deviation 113.68 |
| Placebo | Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Week 26 | 348.3 meters | Standard Deviation 128.82 |
| Placebo | Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Overall change from Baseline to Week 26 | -18.4 meters | Standard Deviation 67.49 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Baseline | 319.1 meters | Standard Deviation 131.41 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Week 26 | 338.8 meters | Standard Deviation 127.06 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Six Minute Walk Test (6MWT) | Overall change from Baseline to Week 26 | 19.7 meters | Standard Deviation 68.56 |
Secondary
Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM)
Active Joint Range of Motion (ROM): Shoulder Flexion Ability to maximally raise one's arm overhead without assistance. Shoulder range of motion (mean of left and right arms) measured in degrees (0-180) by goniometry. Greater degree of flexion indicates greater response.
Time frame: Baseline to Week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Baseline | 89.8 Degrees | Standard Deviation 23.99 |
| Placebo | Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Week 26 | 85.2 Degrees | Standard Deviation 32.66 |
| Placebo | Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Overall change from baseline to week 26 | -4.6 Degrees | Standard Deviation 27.18 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Baseline | 96.1 Degrees | Standard Deviation 30.25 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Week 26 | 88.9 Degrees | Standard Deviation 37.69 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Active Joint Range of Motion (ROM) | Overall change from baseline to week 26 | -1.2 Degrees | Standard Deviation 29.78 |
Secondary
Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI)
Apnea/Hypopnea Index (AHI): Number of absent (apnea) and shallow (hypopnea) breaths per hour of sleep. Overall change from Baseline to Week 26 in AHI. A greater decrease in events indicates a greater response.
Time frame: Baseline to Week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Baseline | 14.7 Events per hour | Standard Deviation 15.2 |
| Placebo | Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Week 26 | 15.5 Events per hour | Standard Deviation 14.93 |
| Placebo | Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Overall change from Baseline to Week 26 | 0.4 Events per hour | Standard Deviation 8.55 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Baseline | 20.5 Events per hour | Standard Deviation 19.04 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Week 26 | 17.6 Events per hour | Standard Deviation 16.75 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Apnea/Hypopnea Index (AHI) | Overall change from Baseline to Week 26 | -2.9 Events per hour | Standard Deviation 6.66 |
Secondary
Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score
CHAQ/HAQ) = Patient questionnaire that measures the degree of disability on a scale of 0 (no disability) to 3 (maximal disability). A lower score indicates a greater response.
Time frame: Baseline to week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Baseline | 1.9 Units on a scale | Standard Deviation 0.6 |
| Placebo | Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Week 26 | 1.8 Units on a scale | Standard Deviation 0.71 |
| Placebo | Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Overall change from Baseline to Week 26 | -0.1 Units on a scale | Standard Deviation 0.43 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Baseline | 2.0 Units on a scale | Standard Deviation 0.49 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Week 26 | 1.9 Units on a scale | Standard Deviation 0.58 |
| Aldurazyme Treatment | Overall Change From Baseline to Week 26 in Child Health Assessment Questionnaire/Health Assessment Questionnaire (CHAQ/HAQ) Disability Index Score | Overall change from Baseline to Week 26 | -0.2 Units on a scale | Standard Deviation 0.39 |
Secondary
Overall Percent Change From Baseline to Week 26 in Liver Volume
Liver Organ Volume: Volume of liver measured by Magnetic Resonance Imaging (MRI). Greater decrease in volume indicates a greater response.
Time frame: Baseline to Week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Percent Change From Baseline to Week 26 in Liver Volume | Baseline | 1368.1 Cubic centimeters | Standard Deviation 314.88 |
| Placebo | Overall Percent Change From Baseline to Week 26 in Liver Volume | Week 26 | 1366.5 Cubic centimeters | Standard Deviation 316.94 |
| Placebo | Overall Percent Change From Baseline to Week 26 in Liver Volume | Overall percent change from Baseline to Week 26 | 1.3 Cubic centimeters | Standard Deviation 19.22 |
| Aldurazyme Treatment | Overall Percent Change From Baseline to Week 26 in Liver Volume | Baseline | 12212.2 Cubic centimeters | Standard Deviation 283.36 |
| Aldurazyme Treatment | Overall Percent Change From Baseline to Week 26 in Liver Volume | Week 26 | 979.8 Cubic centimeters | Standard Deviation 321.45 |
| Aldurazyme Treatment | Overall Percent Change From Baseline to Week 26 in Liver Volume | Overall percent change from Baseline to Week 26 | -18.9 Cubic centimeters | Standard Deviation 19.44 |
Secondary
Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels
Urinary Glycosaminoglycan (GAG) Levels: Concentration of GAG relative to creatinine in urine. A greater decrease in GAG level indicates a greater response.
Time frame: Baseline to Week 26
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Baseline | 183.3 ug/mg | Standard Deviation 72.05 |
| Placebo | Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Week 26 | 250.2 ug/mg | Standard Deviation 105.09 |
| Placebo | Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Overall Percentage of Change in GAG Level | 47.3 ug/mg | Standard Deviation 59.34 |
| Aldurazyme Treatment | Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Baseline | 188.9 ug/mg | Standard Deviation 60.93 |
| Aldurazyme Treatment | Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Week 26 | 81.3 ug/mg | Standard Deviation 26.36 |
| Aldurazyme Treatment | Overall Percent Change From Baseline to Week 26 in Urinary Glycosaminoglycan (GAG) Levels | Overall Percentage of Change in GAG Level | -54.1 ug/mg | Standard Deviation 19.49 |