Hurler-Scheie Syndrome, Hurler Syndrome, Mucopolysaccharidosis I, Scheie Syndrome
Conditions
Brief summary
The main objectives of this study are to evaluate the safety and pharmacokinetics (PK) of enzyme replacement therapy with recombinant human alpha-L-iduronidase \[Aldurazyme® (laronidase)\] in mucopolysaccharidosis I (MPS I) patients less than 5 years old. Efficacy measurements will also be evaluated in this study.
Interventions
100 U/kg every week
Sponsors
BioMarin/Genzyme LLC
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 5 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent is required from the parent(s) or legal guardian(s) prior to any protocol-related procedures being performed. (A separate informed consent will be requested from the parent(s) for their genotyping, which is independent of the inclusion.) * Be less than 5 years of age at the time of enrollment. * Have confirmed iduronidase deficiency with a fibroblast or leukocyte alpha-L-iduronidase enzyme activity level of less than 10.0 % of the lower limit of the normal range, or below the detection range of the measuring laboratory. * Have a clinical diagnosis of MPS I based on genotyping. * Documentation in his/her medical record that the parent(s) or legal guardian(s) have had counseling or a consultation regarding HSCT in order to assure that the parent(s) or legal guardian(s) are fully informed regarding the risks and benefits of this alternative treatment for patients eligible for the trial and with the severe manifestations of MPS I with neurodegeneration.
Exclusion criteria
* The patient is under consideration for or has undergone hematopoietic stem cell transplantation (HSCT). * The patient has acute hydrocephalus at the time of enrollment. * The patient has a clinically significant organic disease (with the exception of symptoms relating to MPS I) including: cardiovascular, hepatic, pulmonary, neurologic, or renal disease, other serious intercurrent illness, or extenuating circumstances that, in the opinion of the Investigator, would preclude participation in the trial or potentially decrease survival. * The patient has received any investigational product within 30 days prior to trial enrollment. * The patient has known severe hypersensitivity to Aldurazyme® (laronidase) or components of the delivery solution.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Evaluation | 52 weeks | Overall Safety Summary of Adverse Events (AEs) during Treatment Safety assessment was based on the incidence of AE reports. |
| Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞) | 52 weeks | AUC∞ is a measure of the total exposure to a drug. |
| Pharmacokinetics - Elimination Half Life (t1/2) | 52 weeks | Half-life is the time it takes for the concentration of drug in plasma to decline by 50%. |
| Pharmacokinetics - Total Plasma Clearance (CL) | 52 weeks | CL is volume of the body fluid cleared of the drug per unit of time. |
| Pharmacokinetics - Volume of Distribution (Vz) | 52 weeks | Vz is the volume that relates the amount of drug in the body after absorption is complete to the concentration of drug in the plasma. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 52 in Height | Baseline to 52 weeks | Change in Z-scores for standing height/lying-length-for-age from Baseline to Week 52. Z-score=number of standard deviations from mean. Z-scores greater than +2 and less than -2 are abnormal. A greater decrease in abnormally high z-score indicates a greater response. |
| Percent Change From Baseline to Week 52 in Urinary Glycosaminoglycan (uGAG) Level | Baseline to 52 weeks | Percentage change in the concentration of GAG relative to creatinine (ug GAG/mg creatinine) in urine from Baseline to Week 52; A greater decrease in percent change indicates a greater response. |
| Investigator's Clinical Assessment at Week 52 Compared With Baseline | Baseline to 52 weeks | The Investigator's impression of the patient's overall clinical status at Week 52 compared with Baseline. |
| Percent Change From Baseline to Week 52 in Liver Size (Hepatomegaly) | Baseline to 52 weeks | Percent change in extent of Liver Edge Below Right Costal Margin (BRCM) measured in centimeters from Baseline to Week 52; A greater decrease in percent change indicates a greater response. |
| Change From Baseline to Week 52 in Apnea/Hypopnea Index (AHI) | Baseline to 52 weeks | Number of absent (apnea) and shallow (hypopnea) breaths per hour of sleep. A greater decrease in events per hour indicates a greater response. |
| Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Baseline to 52 weeks | Independent experts provided a global assessment for each sleep study visit as well as the degree of clinically meaningful change over the course of the study. Assessment was based on AHI, severity and frequency of oxygen desaturations and sleep quality. |
| Change From Baseline to Week 52 in Left Ventricular Mass (LVM) Z-Score | Baseline to 52 weeks | Change in LVM Z-scores as measured by echocardiography from Baseline to Week 52. Z-score=number of standard deviations from mean. Z-scores greater than +2 and less than -2 are abnormal. A greater decrease in abnormally high z-score indicates a greater response. |
Countries
France, Germany, Netherlands, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arms 1 and 2 Combined | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 0 |
Baseline characteristics
| Characteristic | Arms 1 and 2 Combined |
|---|---|
| Age, Continuous | 2.9 years STANDARD_DEVIATION 1.48 |
| Race/Ethnicity, Customized Black | 1 participants |
| Race/Ethnicity, Customized Caucasian | 18 participants |
| Race/Ethnicity, Customized Other | 1 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 15 / 20 |
Outcome results
Primary
Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞)
AUC∞ is a measure of the total exposure to a drug.
Time frame: 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞) | Week 1 | 0.577 hours units/milliliters | Standard Deviation 0.591 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞) | Week 13 | 0.418 hours units/milliliters | Standard Deviation 0.246 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞) | Week 26 | 0.92 hours units/milliliters | Standard Deviation 0.68 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞) | Week 52 | 0.94 hours units/milliliters | Standard Deviation 0.97 |
Primary
Pharmacokinetics - Elimination Half Life (t1/2)
Half-life is the time it takes for the concentration of drug in plasma to decline by 50%.
Time frame: 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Elimination Half Life (t1/2) | Week 1 | 1.55 hours | Standard Deviation 0.516 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Elimination Half Life (t1/2) | Week 13 | 0.55 hours | Standard Deviation 0.284 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Elimination Half Life (t1/2) | Week 26 | 0.946 hours | Standard Deviation 0.877 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Elimination Half Life (t1/2) | Week 52 | 1.147 hours | Standard Deviation 0.87 |
Primary
Pharmacokinetics - Total Plasma Clearance (CL)
CL is volume of the body fluid cleared of the drug per unit of time.
Time frame: 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Total Plasma Clearance (CL) | Week 1 | 5.73 (milliliters/minute)/kilograms | Standard Deviation 3.9 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Total Plasma Clearance (CL) | Week 13 | 5.33 (milliliters/minute)/kilograms | Standard Deviation 2.67 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Total Plasma Clearance (CL) | Week 26 | 2.97 (milliliters/minute)/kilograms | Standard Deviation 1.87 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Total Plasma Clearance (CL) | Week 52 | 3.20 (milliliters/minute)/kilograms | Standard Deviation 2.02 |
Primary
Pharmacokinetics - Volume of Distribution (Vz)
Vz is the volume that relates the amount of drug in the body after absorption is complete to the concentration of drug in the plasma.
Time frame: 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Volume of Distribution (Vz) | Week 1 | 0.753 liters/kilograms | Standard Deviation 0.497 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Volume of Distribution (Vz) | Week 13 | 0.299 liters/kilograms | Standard Deviation 0.303 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Volume of Distribution (Vz) | Week 26 | 0.214 liters/kilograms | Standard Deviation 0.297 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Pharmacokinetics - Volume of Distribution (Vz) | Week 52 | 0.246 liters/kilograms | Standard Deviation 0.21 |
Primary
Safety Evaluation
Overall Safety Summary of Adverse Events (AEs) during Treatment Safety assessment was based on the incidence of AE reports.
Time frame: 52 weeks
Population: The number of participants was determined as adequate to assess the safety of Aldurazyme in young children with mucopolysaccharidosis I (MPS I). The analysis was intent-to-treat.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Safety Evaluation | Having Adverse Events (AE) | 16 participants | 21.41 |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Safety Evaluation | Deaths/Discontinuations Due to AEs | 2 participants | — |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Safety Evaluation | Having Drug-Related AEs | 5 participants | — |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Safety Evaluation | Having Serious AEs | 12 participants | — |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Safety Evaluation | Having Severe AEs | 5 participants | — |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Safety Evaluation | Having Infusion Associated Reactions (IAR): | 4 participants | — |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Safety Evaluation | Deaths/Discontinuations Due to AEs | 0 participants | — |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Safety Evaluation | Having Adverse Events (AE) | 4 participants | 14.21 |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Safety Evaluation | Having Infusion Associated Reactions (IAR): | 3 participants | — |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Safety Evaluation | Having Severe AEs | 1 participants | — |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Safety Evaluation | Having Serious AEs | 3 participants | — |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Safety Evaluation | Having Drug-Related AEs | 3 participants | — |
Other Pre-specified
Change From Baseline to Week 52 in Apnea/Hypopnea Index (AHI)
Number of absent (apnea) and shallow (hypopnea) breaths per hour of sleep. A greater decrease in events per hour indicates a greater response.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Change From Baseline to Week 52 in Apnea/Hypopnea Index (AHI) | -2.6 Events per hour | Standard Deviation 22.27 |
Other Pre-specified
Change From Baseline to Week 52 in Height
Change in Z-scores for standing height/lying-length-for-age from Baseline to Week 52. Z-score=number of standard deviations from mean. Z-scores greater than +2 and less than -2 are abnormal. A greater decrease in abnormally high z-score indicates a greater response.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Change From Baseline to Week 52 in Height | -0.5 Units on a scale | Standard Deviation 0.93 |
Other Pre-specified
Change From Baseline to Week 52 in Left Ventricular Mass (LVM) Z-Score
Change in LVM Z-scores as measured by echocardiography from Baseline to Week 52. Z-score=number of standard deviations from mean. Z-scores greater than +2 and less than -2 are abnormal. A greater decrease in abnormally high z-score indicates a greater response.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Change From Baseline to Week 52 in Left Ventricular Mass (LVM) Z-Score | -0.9 Units on a scale | Standard Deviation 1.58 |
Other Pre-specified
Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline
Independent experts provided a global assessment for each sleep study visit as well as the degree of clinically meaningful change over the course of the study. Assessment was based on AHI, severity and frequency of oxygen desaturations and sleep quality.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Marked Improvement | 1 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Moderate Improvement | 3 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Mild Improvement | 1 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | No change | 5 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Slight Worsening | 3 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Moderate Worsening | 1 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline | Marked Worsening | 1 participants |
Other Pre-specified
Investigator's Clinical Assessment at Week 52 Compared With Baseline
The Investigator's impression of the patient's overall clinical status at Week 52 compared with Baseline.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | Marked Worsening | 0 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | Marked Improvement | 0 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | Moderate Improvement | 6 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | Mild Improvement | 11 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | No Change | 1 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | Slight Worsening | 0 participants |
| Aldurazyme (rhIDU) 100 U/kg Every Week | Investigator's Clinical Assessment at Week 52 Compared With Baseline | Moderate Worsening | 0 participants |
Other Pre-specified
Percent Change From Baseline to Week 52 in Liver Size (Hepatomegaly)
Percent change in extent of Liver Edge Below Right Costal Margin (BRCM) measured in centimeters from Baseline to Week 52; A greater decrease in percent change indicates a greater response.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Percent Change From Baseline to Week 52 in Liver Size (Hepatomegaly) | -69.5 Percentage of change | Standard Deviation 15.34 |
Other Pre-specified
Percent Change From Baseline to Week 52 in Urinary Glycosaminoglycan (uGAG) Level
Percentage change in the concentration of GAG relative to creatinine (ug GAG/mg creatinine) in urine from Baseline to Week 52; A greater decrease in percent change indicates a greater response.
Time frame: Baseline to 52 weeks
Population: The analysis was intent-to-treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aldurazyme (rhIDU) 100 U/kg Every Week | Percent Change From Baseline to Week 52 in Urinary Glycosaminoglycan (uGAG) Level | -59.1 Percentage of change | Standard Deviation 21.41 |
| Aldurazyme (rhIDU) 100-200 U/kg Every Week | Percent Change From Baseline to Week 52 in Urinary Glycosaminoglycan (uGAG) Level | -67.7 Percentage of change | Standard Deviation 14.21 |