Hunter Syndrome, MPS II, Mucopolysaccharidosis II
Conditions
Keywords
Hunter syndrome, hunters syndrome, hunter's syndrome, hunter disease, hunters disease, hunter's disease, MPS II, MPSII, MPS2, MPS 2, mucopolysaccharides, lysosomal storage disease, lysosomal storage disorder, chronic ear infection, enlarged adenoids, mps symptoms, mps diagnosis, mps ii therapy, MPS II treatment, ert treatment, elaprase, idursulfase, iduronate sulfatase, iduronate 2 sulfatase, enzyme replacement therapy, hunter syndrome treatment, hunter's syndrome treatment, hunter syndrome therapy, hunter's disease treatment, mps society
Brief summary
The objective of this study is to determine the safety of once weekly dosing of idursulfase 0.5 mg/kg administered by intravenous (IV) infusion for male Hunter syndrome patients ≤ 5 years old.
Detailed description
This study will provide a basis for evaluating the safety of idursulfase administered to Hunter syndrome patients who are ≤ 5 years old. Additionally, this study will provide a basis for evaluating the idursulfase single- and repeated-dose pharmacokinetic profiles as well as the pharmacodynamic effect (as measured by urinary GAG excretion) in this pediatric population. Additional exploratory measures will include abdominal ultrasound measurements of liver and spleen volumes, assessments of growth with comparisons to normal population growth data, assessments of annualized growth velocity, assessments of routine developmental milestones using the Denver II, and assessments of clinical events, including the first occurrence of certain hearing-related events (e.g., hearing loss, otitis media), respiratory-related events (e.g., upper and lower respiratory infections), and specific surgical procedures (e.g., adenoidectomy, placement of PE tubes). All patients in this open-label study will receive once-weekly infusions of idursulfase at a dose of 0.5 mg/kg.
Interventions
BIOLOGICALIdursulfase
Solution for intravenous infusion, 0.5 mg/kg weekly
Sponsors
Covance
PharmaNet
PRA Health Sciences
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 5 Years
Healthy volunteers
No
Inclusion criteria
* The patient has a diagnosis of Hunter syndrome based upon biochemical criteria either documented in their medical history or established at Screening: 1. A deficiency in iduronate-2-sulfatase (I2S) enzyme activity of ≤ 10 % of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory) AND 2. A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory). * The patient is 5 years of age and under. * The patient is male. * The patient's parent(s), or patient's legal guardian must have voluntarily signed an Institutional Review Board approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's parent(s), or the patient's legal guardian.
Exclusion criteria
* The patient has received treatment with another investigational therapy within 30 days prior to enrollment. * The patient has clinically relevant medical condition(s) making implementation of the protocol difficult. * The patient has previously received idursulfase. * The patient has known hypersensitivity to any of the components of idursulfase. * The patient has had a tracheostomy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Evaluation | From the start of study treatment until 30 days after the last infusion of idursulfase, up to 53 weeks | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Number of participants with AEs occurred after start of study treatment until 30 days after the last infusion of idursulfase, were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax) | Weeks 1 and 27 | — |
| Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax) | Weeks 1 and 27 | — |
| Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to the Final Time Point With a Concentration of at Least Lower Limit of Quantitation (AUClast) | Weeks 1 and 27 | — |
| Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) | Weeks 1 and 27 | — |
| Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels | Baseline, Weeks 18, 36 and 53 | Analysis of urinary GAG levels was performed at baseline, Week 18, Week 36, and Week 53 as an assessment of the pharmacodynamic effects of Elaprase (idursulfase). |
| Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time From Time 0 to Infinity (MRTinf) | Weeks 1 and 27 | MRTinf is an average duration of the drug in the body from time zero to infinity, and is expressed in minutes. |
| Single- and Repeat-Dose Pharmacokinetics - Clearance (CL) | Weeks 1 and 27 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss) | Weeks 1 and 27 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate. |
| Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2) | Weeks 1 and 27 | t1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in minutes and derived from the terminal slope of the concentration versus time curve. |
Countries
Brazil, Poland, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Idursulfase Open-label treatment with idursulfase | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Idursulfase |
|---|---|
| Age, Continuous | 4.0 years STANDARD_DEVIATION 1.62 |
| Baseline Normalized Urinary Glycosaminoglycan (GAG) Level | 738.3 microgram per milligram creatinine STANDARD_DEVIATION 165.21 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 28 |
| serious Total, serious adverse events | 13 / 28 |
Outcome results
Primary
Safety Evaluation
An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Number of participants with AEs occurred after start of study treatment until 30 days after the last infusion of idursulfase, were reported.
Time frame: From the start of study treatment until 30 days after the last infusion of idursulfase, up to 53 weeks
Population: Safety population was defined as all enrolled participants who received at least one study dose (or any portion of a dose) of idursulfase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Idursulfase | Safety Evaluation | Experienced at least one drug-related AE | 16 participants |
| Idursulfase | Safety Evaluation | Experienced at least one adverse event (AE) | 28 participants |
| Idursulfase | Safety Evaluation | Deaths | 0 participants |
| Idursulfase | Safety Evaluation | Discontinued due to an AE | 0 participants |
| Idursulfase | Safety Evaluation | Experienced at least one serious AE (SAE) | 13 participants |
| Idursulfase | Safety Evaluation | Experienced at least one severe AE | 2 participants |
| Idursulfase | Safety Evaluation | Experienced at least one infusion-related AE | 16 participants |
Secondary
Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels
Analysis of urinary GAG levels was performed at baseline, Week 18, Week 36, and Week 53 as an assessment of the pharmacodynamic effects of Elaprase (idursulfase).
Time frame: Baseline, Weeks 18, 36 and 53
Population: Safety population. In the categories listed below, 'N' signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels | Baseline (N=28) | 738.3 microgram/milligram creatinine | Standard Deviation 165.21 |
| Idursulfase | Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels | Change at Week 18 (N=27) | -368.0 microgram/milligram creatinine | Standard Deviation 165.44 |
| Idursulfase | Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels | Change at Week 36 (N=27) | -400.3 microgram/milligram creatinine | Standard Deviation 180.27 |
| Idursulfase | Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels | Change at Week 53 (N=27) | -402.4 microgram/milligram creatinine | Standard Deviation 162.13 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf)
Time frame: Weeks 1 and 27
Population: PK population with evaluable participants for this endpoint. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) | Week 1 (N=26) | 224343 minute*nanogram per milliliter | Standard Deviation 76944 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) | Week 27 (N=18) | 201130 minute*nanogram per milliliter | Standard Deviation 117575 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to the Final Time Point With a Concentration of at Least Lower Limit of Quantitation (AUClast)
Time frame: Weeks 1 and 27
Population: PK population. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to the Final Time Point With a Concentration of at Least Lower Limit of Quantitation (AUClast) | Week 1 (N=27) | 196526 minute*nanogram per milliliter | Standard Deviation 71779 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to the Final Time Point With a Concentration of at Least Lower Limit of Quantitation (AUClast) | Week 27 (N=19) | 174869 minute*nanogram per milliliter | Standard Deviation 109118 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Clearance (CL)
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Weeks 1 and 27
Population: PK population with evaluable participants for this endpoint. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Clearance (CL) | Week 1 (N=26) | 2.4 milliliter/minute/kilogram | Standard Deviation 0.7 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Clearance (CL) | Week 27 (N=18) | 4.7 milliliter/minute/kilogram | Standard Deviation 5 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2)
t1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in minutes and derived from the terminal slope of the concentration versus time curve.
Time frame: Weeks 1 and 27
Population: PK population with evaluable participants for this endpoint. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2) | Week 1 (N=26) | 160 minutes | Standard Deviation 69 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2) | Week 27 (N=18) | 109 minutes | Standard Deviation 43 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax)
Time frame: Weeks 1 and 27
Population: Pharmacokinetic (PK) population was defined as all enrolled participants who had at least one serum concentration measurement available. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax) | Week 1 (N=27) | 1333 nanogram per milliliter | Standard Deviation 817 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax) | Week 27 (N=19) | 1032 nanogram per milliliter | Standard Deviation 590 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time From Time 0 to Infinity (MRTinf)
MRTinf is an average duration of the drug in the body from time zero to infinity, and is expressed in minutes.
Time frame: Weeks 1 and 27
Population: PK population with evaluable participants for this endpoint. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time From Time 0 to Infinity (MRTinf) | Week 1 (N=26) | 153 minutes | Standard Deviation 96 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time From Time 0 to Infinity (MRTinf) | Week 27 (N=18) | 127 minutes | Standard Deviation 23 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax)
Time frame: Weeks 1 and 27
Population: PK population. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax) | Week 1 (N=27) | 163 minutes | Standard Deviation 28 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax) | Week 27 (N=19) | 167 minutes | Standard Deviation 32 |
Secondary
Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.
Time frame: Weeks 1 and 27
Population: PK population with evaluable participants for this endpoint. In the categories listed below, N signifies the number of participants evaluable for the timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss) | Week 1 (N=26) | 394 milliliter per kilogram | Standard Deviation 423 |
| Idursulfase | Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss) | Week 27 (N=18) | 551 milliliter per kilogram | Standard Deviation 528 |