Hunter Syndrome
Conditions
Keywords
MPS II, MPS 2, lysosomal storage disorder, mps symptoms, enlarged adenoids, elaprase, hunter's syndrome, MPS2, hunters disease, hunter's disease treatment, hunter syndrome therapy, iduronate sulfatase, mps society, MPSII, hunter syndrome treatment, hunter's disease, iduronate 2 sulfatase, mucopolysaccharides, mps diagnosis, chronic ear infection, hunters syndrome, ert treatment, lysosomal storage disease, hunter disease, enzyme replacement therapy, idursulfase, hunter's syndrome treatment
Brief summary
This extension study of HGT-HIT-045 is designed to collect long-term safety data in pediatric participants with Hunter syndrome and cognitive impairment who are receiving intrathecal (IT) idursulfase-IT and intravenous (IV) Elaprase enzyme replacement therapy.
Interventions
DRUGIdursulfase-IT
Idursulfase-IT once monthly via IDDD.
DRUGElaprase
Weekly IV infusions of commercially available Elaprase.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
3 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria Inclusion Criteria: * Participant must have completed all study requirements and End of study (EOS) assessments for study HGT-HIT-045 (NCT00920647) prior to enrolling in Study HGT-HIT-046 and must have no safety or medical issues that contraindicate participation. * The participant's parent(s) or legally authorized guardian(s) 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. Consent of the participant's parent(s) or legally authorized guardian(s) and the participant's assent, as relevant, must be obtained. * The participant has received and tolerated a minimum of 12 months of treatment with weekly IV infusions of Elaprase and has received 80% of the total planned infusions within the last 6 months.
Exclusion criteria
* The participant is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or device) other than the PORT-A-CATH IDDD within 30 days prior to study enrollment or at any time during the study. * The participant is unable to comply with the protocol (eg, is unable to return for safety evaluations, or is otherwise unlikely to complete the study) as determined by the investigator. * The participant has experienced an adverse reaction to study drug in Study HGT-HIT-045 (NCT00920647) that contraindicates further treatment with intrathecal idursulfase-IT. * The participant has a known hypersensitivity to any of the components of idursulfase-IT. * The participant has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions. * The participant has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use, including: 1. The participant has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device 2. The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the investigator 3. The participant's drug therapy requires substances known to be incompatible with the materials of construction 4. The participant has a known or suspected local or general infection 5. The participant is at risk of abnormal bleeding due to a medical condition or therapy 6. The participant has one or more spinal abnormalities that could complicate safe implantation or fixation 7. The participant has a functioning CSF shunt device 8. The participant has shown an intolerance to an implanted device An additional exclusion criterion for patients who were previously untreated with intrathecal idursulfase-IT in Study HGT-HIT-045 (NCT00920647): * The participant has an opening CSF pressure upon lumbar puncture that exceeds 30.0 centimeter (cm) water (H2O).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From start of study drug administration up to follow-up (up to 165 months) | An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, and/or laboratory changes occurring in any phase of a clinical trial, and whether or not considered study drug-related. TEAEs were defined as all AEs occurring on or after the first IDDD surgery date or first dose (whichever is earlier) for the participant (whether it is in this extension study or in HGT HIT-045 \[NCT00920647\]) and before the end of the study (EOS) visit (+30 days). For Idursulfase-IT 1 mg+10 mg arm the summary presented includes only the TEAEs that occurred while the participants were assigned to 10 mg. |
| Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in Laboratory Parameters | From start of study drug administration up to follow-up (up to 165 months) | Number of participants with clinically significant changes in laboratory parameters (chemistry, hematology, urinalysis and CSF values) were collected. |
| Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in 12-lead Electrocardiogram (ECG) Findings | From start of study drug administration up to follow-up (up to 165 months) | Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) findings (heart rate, PR interval, QRS interval, QT interval and the corrected QT interval) were collected. |
| CSF Chemistries: Change From Baseline in CSF Total Cell Count | Baseline, Month 163 | — |
| CSF Chemistries: Change From Baseline in CSF Glucose | Baseline, Month 163 | — |
| CSF Chemistries: Change From Baseline in CSF Protein | Baseline, Month 163 | — |
| Number of Participants With Anti-idursulfase Antibodies in CSF | From start of study drug administration up to follow-up (up to 165 months) | — |
| Number of Participants With Anti-idursulfase Antibodies in Serum | From start of study drug administration up to follow-up (up to 165 months) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Body Clearance (CL) of Elaprase | 15 minutes prior to IV infusion, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 9, 11, and 24 hours during/after the IV infusion on Days 3-7 of Weeks 3 and 23 | — |
| Observed Steady-state Volume of Distribution (Vss) of Elaprase | 15 minutes prior to IV infusion and at multiple timepoint (0.5, 1, 1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours) following IV infusion on Days 3-7 of Weeks 3 and 23 | — |
| Volume of Distribution (Vz) of Elaprase | 15 minutes prior to IV infusion and at multiple timepoints (0.5, 1, 1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours) following IV infusion on Days 3-7 of Weeks 3 and 23 | Volume of distribution associated with the terminal slope (Vz) of Elaprase was assessed. |
| Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Area under the curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration (AUC0-infinity) of idursulfase was assessed. Participants in 1 mg arm group were assessed for Pharmacokinetic (PK) analysis in the HGT-HIT-045 study. |
| Change From Baseline in CSF Biomarkers | Baseline, Months 7, 55, and 139 | Change from baseline in CSF biomarkers glycosaminoglycan (GAG \[heparan sulfate (HS)/dermatan sulfate (DS)\]) was assessed. |
| Change From Baseline in Urinary Glycosaminoglycan (GAG) | Baseline, Months 7, 55, and 163 | mg GAG/mmol creatinine stands for milligrams of GAG per millimole of creatinine. |
| Mean Residence Time Extrapolated to Infinity (MRT0-inf) of Elaprase | 15 minutes prior to IV infusion and at multiple timepoints (0.5, 1, 1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours) following IV infusion on Days 3-7 of Weeks 3 and 23 | — |
| Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. |
| Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. |
| Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. |
| Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. |
| Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. |
| First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. |
| Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups | Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. T1/2 is calculated by dividing 0.693 by Lambda z. Here, 0.693 is the natural logarithm of 2 and Lambda z is the first order rate constant. |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at various investigative sites in the United States (US) and the United Kingdom (UK) from 01 August 2010 to 30 April 2024.
Pre-assignment details
15 participants who completed the Study HGT-HIT-045 (NCT00920647) received idursulfase-IT in conjunction with Elaprase therapy. Participants who received idursulfase-IT treatment in study HGT-HIT-045, initiated treatment at the same dose level and were analyzed as per the reference timepoints of HGT-HIT-045 for some evaluations. For others, the reference timepoints after enrollment to this extension study were considered.
Participants by arm
| Arm | Count |
|---|---|
| Idursulfase-IT 1 mg Participants received 1 mg idursulfase-IT intrathecally via IDDD or LP once monthly and SoC therapy of Elaprase IV infusions for up to a maximum of 10.1 months. | 4 |
| Idursulfase-IT 10 mg Participants received 10 mg idursulfase-IT initially intrathecally via IDDD or LP once monthly and SoC therapy of Elaprase IV infusions for up to a maximum of 157.2 months. | 6 |
| Idursulfase-IT 30 mg Participants received 30 mg idursulfase-IT intrathecally via IDDD or LP once monthly and SoC therapy of Elaprase IV infusions for up to a maximum of 148.2 months. | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Participation Terminated by Investigator | 1 | 1 |
| Overall Study | Reason Not Specified | 4 | 2 |
| Overall Study | Site Terminated by Sponsor | 2 | 0 |
Baseline characteristics
| Characteristic | Idursulfase-IT 1 mg | Idursulfase-IT 10 mg | Idursulfase-IT 30 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 5.61 years STANDARD_DEVIATION 1.799 | 5.68 years STANDARD_DEVIATION 2.501 | 7.94 years STANDARD_DEVIATION 2.706 | 6.41 years STANDARD_DEVIATION 2.502 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 10 | 0 / 5 |
| other Total, other adverse events | 4 / 4 | 10 / 10 | 5 / 5 |
| serious Total, serious adverse events | 3 / 4 | 9 / 10 | 4 / 5 |
Outcome results
Primary
CSF Chemistries: Change From Baseline in CSF Glucose
Time frame: Baseline, Month 163
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study. Overall number analyzed are the number of participants who had data at Baseline. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | CSF Chemistries: Change From Baseline in CSF Glucose | Baseline | 2.950 millimoles per liter (mmol/L) | Standard Deviation 0.265 |
| Idursulfase-IT 10 mg | CSF Chemistries: Change From Baseline in CSF Glucose | Change from Baseline in CSF Glucose at Month 163 | 0.523 millimoles per liter (mmol/L) | Standard Deviation 0.436 |
| Idursulfase-IT 10 mg | CSF Chemistries: Change From Baseline in CSF Glucose | Baseline | 2.850 millimoles per liter (mmol/L) | Standard Deviation 0.217 |
| Idursulfase-IT 30 mg | CSF Chemistries: Change From Baseline in CSF Glucose | Baseline | 3.000 millimoles per liter (mmol/L) | Standard Deviation 0.2 |
Primary
CSF Chemistries: Change From Baseline in CSF Protein
Time frame: Baseline, Month 163
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study. Overall number analyzed are the number of participants who had data at Baseline. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | CSF Chemistries: Change From Baseline in CSF Protein | Baseline | 0.400 grams per liter (g/L) | Standard Deviation 0.194 |
| Idursulfase-IT 10 mg | CSF Chemistries: Change From Baseline in CSF Protein | Baseline | 0.282 grams per liter (g/L) | Standard Deviation 0.144 |
| Idursulfase-IT 10 mg | CSF Chemistries: Change From Baseline in CSF Protein | Change from Baseline in CSF Protein at Month 163 | 0.493 grams per liter (g/L) | Standard Deviation 0.229 |
| Idursulfase-IT 30 mg | CSF Chemistries: Change From Baseline in CSF Protein | Baseline | 0.530 grams per liter (g/L) | Standard Deviation 0.368 |
Primary
CSF Chemistries: Change From Baseline in CSF Total Cell Count
Time frame: Baseline, Month 163
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study. Overall number analyzed are the number of participants who had data at Baseline. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | CSF Chemistries: Change From Baseline in CSF Total Cell Count | Baseline | 1.0 10^6 cells/Liter (L) | Standard Deviation 0 |
| Idursulfase-IT 10 mg | CSF Chemistries: Change From Baseline in CSF Total Cell Count | Baseline | 1.0 10^6 cells/Liter (L) | Standard Deviation 0 |
| Idursulfase-IT 10 mg | CSF Chemistries: Change From Baseline in CSF Total Cell Count | Change From Baseline in CSF Total Cell Count at Month 163 | 7.3 10^6 cells/Liter (L) | Standard Deviation 11.85 |
| Idursulfase-IT 30 mg | CSF Chemistries: Change From Baseline in CSF Total Cell Count | Baseline | 1.0 10^6 cells/Liter (L) | Standard Deviation 0 |
Primary
Number of Participants With Anti-idursulfase Antibodies in CSF
Time frame: From start of study drug administration up to follow-up (up to 165 months)
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idursulfase-IT 1 mg | Number of Participants With Anti-idursulfase Antibodies in CSF | At Baseline | 3 Participants |
| Idursulfase-IT 1 mg | Number of Participants With Anti-idursulfase Antibodies in CSF | Post-Baseline | 3 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Anti-idursulfase Antibodies in CSF | At Baseline | 1 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Anti-idursulfase Antibodies in CSF | Post-Baseline | 5 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Anti-idursulfase Antibodies in CSF | At Baseline | 1 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Anti-idursulfase Antibodies in CSF | Post-Baseline | 1 Participants |
Primary
Number of Participants With Anti-idursulfase Antibodies in Serum
Time frame: From start of study drug administration up to follow-up (up to 165 months)
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idursulfase-IT 1 mg | Number of Participants With Anti-idursulfase Antibodies in Serum | At Baseline | 3 Participants |
| Idursulfase-IT 1 mg | Number of Participants With Anti-idursulfase Antibodies in Serum | Post-Baseline | 3 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Anti-idursulfase Antibodies in Serum | At Baseline | 2 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Anti-idursulfase Antibodies in Serum | Post-Baseline | 6 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Anti-idursulfase Antibodies in Serum | At Baseline | 2 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Anti-idursulfase Antibodies in Serum | Post-Baseline | 3 Participants |
Primary
Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in 12-lead Electrocardiogram (ECG) Findings
Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) findings (heart rate, PR interval, QRS interval, QT interval and the corrected QT interval) were collected.
Time frame: From start of study drug administration up to follow-up (up to 165 months)
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idursulfase-IT 1 mg | Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in Laboratory Parameters
Number of participants with clinically significant changes in laboratory parameters (chemistry, hematology, urinalysis and CSF values) were collected.
Time frame: From start of study drug administration up to follow-up (up to 165 months)
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idursulfase-IT 1 mg | Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in Laboratory Parameters | 0 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in Laboratory Parameters | 0 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in Laboratory Parameters | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, and/or laboratory changes occurring in any phase of a clinical trial, and whether or not considered study drug-related. TEAEs were defined as all AEs occurring on or after the first IDDD surgery date or first dose (whichever is earlier) for the participant (whether it is in this extension study or in HGT HIT-045 \[NCT00920647\]) and before the end of the study (EOS) visit (+30 days). For Idursulfase-IT 1 mg+10 mg arm the summary presented includes only the TEAEs that occurred while the participants were assigned to 10 mg.
Time frame: From start of study drug administration up to follow-up (up to 165 months)
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idursulfase-IT 1 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 4 Participants |
| Idursulfase-IT 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 10 Participants |
| Idursulfase-IT 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 5 Participants |
Secondary
Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase
Area under the curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration (AUC0-infinity) of idursulfase was assessed. Participants in 1 mg arm group were assessed for Pharmacokinetic (PK) analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug \& participated in the scheduled pharmacokinetic studies,\& for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates number of participants with data available for analyses. Number analyzed indicates number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA hours*nanograms per milliliter(h*ng/mL) | — |
| Idursulfase-IT 1 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 1574.37 hours*nanograms per milliliter(h*ng/mL) | — |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 2869 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 563.1 |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 2649 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 1334.8 |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 1865 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 775.2 |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 1765 hours*nanograms per milliliter(h*ng/mL) | — |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 2324 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 203 |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 1636 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 351.4 |
| Idursulfase-IT 10 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 1649 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 167.4 |
| Idursulfase-IT 30 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 3270 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 801.6 |
| Idursulfase-IT 30 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 2445 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 1770.8 |
| Idursulfase-IT 30 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 4766 hours*nanograms per milliliter(h*ng/mL) | — |
| Idursulfase-IT 30 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 5179 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 2579.8 |
| Idursulfase-IT 30 mg | Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 4395 hours*nanograms per milliliter(h*ng/mL) | Standard Deviation 733.1 |
Secondary
Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA h*ng/mL | — |
| Idursulfase-IT 1 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 524.68 h*ng/mL | — |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 1500 h*ng/mL | Standard Deviation 347.1 |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 1356 h*ng/mL | Standard Deviation 235.3 |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 1247 h*ng/mL | Standard Deviation 204 |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | 1214 h*ng/mL | — |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 1047 h*ng/mL | — |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 1633 h*ng/mL | Standard Deviation 976.6 |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 2031 h*ng/mL | Standard Deviation 1081.9 |
| Idursulfase-IT 10 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 1944 h*ng/mL | Standard Deviation 295.8 |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 4855 h*ng/mL | — |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 3586 h*ng/mL | Standard Deviation 1056.9 |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 2415 h*ng/mL | Standard Deviation 394.8 |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 3525 h*ng/mL | Standard Deviation 835.5 |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | 3746 h*ng/mL | — |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 1466 h*ng/mL | Standard Deviation 1511.8 |
| Idursulfase-IT 30 mg | Area Under the Curve From the Time of Dosing to the Last Measureable Concentration (AUC0-t) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 3141 h*ng/mL | Standard Deviation 979.7 |
Secondary
Change From Baseline in CSF Biomarkers
Change from baseline in CSF biomarkers glycosaminoglycan (GAG \[heparan sulfate (HS)/dermatan sulfate (DS)\]) was assessed.
Time frame: Baseline, Months 7, 55, and 139
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and have had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study. Number analyzed is the number of participants with data available for analyses. A few participants from the 1 mg arm had transitioned to 10 mg arm before the analysis at Month 7 was performed for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 7 | -807.50 ng/mL | Standard Deviation 569.461 |
| Idursulfase-IT 1 mg | Change From Baseline in CSF Biomarkers | Baseline | 1922.34 ng/mL | Standard Deviation 1164.679 |
| Idursulfase-IT 10 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 55 | -1575.63 ng/mL | Standard Deviation 906.621 |
| Idursulfase-IT 10 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 139 | -1169.25 ng/mL | Standard Deviation 530.781 |
| Idursulfase-IT 10 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 7 | -1526.24 ng/mL | Standard Deviation 638.893 |
| Idursulfase-IT 10 mg | Change From Baseline in CSF Biomarkers | Baseline | 1874.00 ng/mL | Standard Deviation 979.459 |
| Idursulfase-IT 30 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 139 | -1135.51 ng/mL | — |
| Idursulfase-IT 30 mg | Change From Baseline in CSF Biomarkers | Baseline | 1111.92 ng/mL | Standard Deviation 485.898 |
| Idursulfase-IT 30 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 7 | -987.65 ng/mL | Standard Deviation 437.885 |
| Idursulfase-IT 30 mg | Change From Baseline in CSF Biomarkers | Change from Baseline at Month 55 | -974.07 ng/mL | Standard Deviation 558.075 |
Secondary
Change From Baseline in Urinary Glycosaminoglycan (GAG)
mg GAG/mmol creatinine stands for milligrams of GAG per millimole of creatinine.
Time frame: Baseline, Months 7, 55, and 163
Population: Safety Population included all eligible participants from HGT-HIT-045 who had agreed to participate in the extension study and have had either surgical implantation of an IDDD or intrathecal administration of study drug in the extension study. Number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Baseline | 34.07 mg GAG/mmol creatinine | Standard Deviation 20.132 |
| Idursulfase-IT 1 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from Baseline at Month 7 | 5.22 mg GAG/mmol creatinine | Standard Deviation 6.084 |
| Idursulfase-IT 10 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from Baseline at Month 163 | -13.88 mg GAG/mmol creatinine | Standard Deviation 5.163 |
| Idursulfase-IT 10 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Baseline | 23.35 mg GAG/mmol creatinine | Standard Deviation 13.799 |
| Idursulfase-IT 10 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from Baseline at Month 55 | -6.83 mg GAG/mmol creatinine | Standard Deviation 5.837 |
| Idursulfase-IT 10 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from Baseline at Month 7 | -4.20 mg GAG/mmol creatinine | Standard Deviation 4.278 |
| Idursulfase-IT 30 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from Baseline at Month 55 | 6.33 mg GAG/mmol creatinine | Standard Deviation 7.387 |
| Idursulfase-IT 30 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Baseline | 13.67 mg GAG/mmol creatinine | Standard Deviation 7.2 |
| Idursulfase-IT 30 mg | Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from Baseline at Month 7 | 3.35 mg GAG/mmol creatinine | Standard Deviation 1.324 |
Secondary
First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | NA per hour (/h) | — |
| Idursulfase-IT 1 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA per hour (/h) | — |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 0.0383 per hour (/h) | Standard Deviation 0.0026 |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 0.0539 per hour (/h) | Standard Deviation 0.00831 |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 0.0772 per hour (/h) | Standard Deviation 0.0355 |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 0.0487 per hour (/h) | Standard Deviation 0.01996 |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 0.0309 per hour (/h) | — |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 0.0677 per hour (/h) | Standard Deviation 0.01829 |
| Idursulfase-IT 10 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 0.0486 per hour (/h) | Standard Deviation 0.01126 |
| Idursulfase-IT 30 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 0.0489 per hour (/h) | — |
| Idursulfase-IT 30 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 0.0419 per hour (/h) | Standard Deviation 0.00917 |
| Idursulfase-IT 30 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 0.0455 per hour (/h) | Standard Deviation 0.0086 |
| Idursulfase-IT 30 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 0.0700 per hour (/h) | Standard Deviation 0.01892 |
| Idursulfase-IT 30 mg | First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 0.0649 per hour (/h) | Standard Deviation 0.00708 |
Secondary
Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 19 nanograms per milliliter (ng/mL) | — |
| Idursulfase-IT 1 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA nanograms per milliliter (ng/mL) | — |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 36.10 nanograms per milliliter (ng/mL) | — |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 64.08 nanograms per milliliter (ng/mL) | Standard Deviation 7.835 |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | 43.95 nanograms per milliliter (ng/mL) | — |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 76.39 nanograms per milliliter (ng/mL) | Standard Deviation 51.386 |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 143.52 nanograms per milliliter (ng/mL) | Standard Deviation 122.774 |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 90.57 nanograms per milliliter (ng/mL) | Standard Deviation 28.72 |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 61.50 nanograms per milliliter (ng/mL) | Standard Deviation 19.33 |
| Idursulfase-IT 10 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 56.73 nanograms per milliliter (ng/mL) | Standard Deviation 12.69 |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | 146.75 nanograms per milliliter (ng/mL) | — |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 144.35 nanograms per milliliter (ng/mL) | Standard Deviation 44.434 |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 173.40 nanograms per milliliter (ng/mL) | — |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 99.20 nanograms per milliliter (ng/mL) | Standard Deviation 19.762 |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 156.80 nanograms per milliliter (ng/mL) | Standard Deviation 33.054 |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 93.43 nanograms per milliliter (ng/mL) | Standard Deviation 61.406 |
| Idursulfase-IT 30 mg | Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 175.20 nanograms per milliliter (ng/mL) | Standard Deviation 70.083 |
Secondary
Mean Residence Time Extrapolated to Infinity (MRT0-inf) of Elaprase
Time frame: 15 minutes prior to IV infusion and at multiple timepoints (0.5, 1, 1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours) following IV infusion on Days 3-7 of Weeks 3 and 23
Population: Participants who received only Elaprase in HGT-HIT-045 and had evaluable samples were analyzed for this outcome measure. Number analyzed indicates the number of participants with data available for analyses at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Mean Residence Time Extrapolated to Infinity (MRT0-inf) of Elaprase | Week 3: Day 3-7 | 6.49 hours | Standard Deviation 3.817 |
| Idursulfase-IT 1 mg | Mean Residence Time Extrapolated to Infinity (MRT0-inf) of Elaprase | Week 23: Day 3-7 | 3.80 hours | — |
Secondary
Observed Steady-state Volume of Distribution (Vss) of Elaprase
Time frame: 15 minutes prior to IV infusion and at multiple timepoint (0.5, 1, 1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours) following IV infusion on Days 3-7 of Weeks 3 and 23
Population: Participants who received only Elaprase in HGT-HIT-045 and had evaluable samples were analyzed for this outcome measure. Number analyzed indicates the number of participants with data available for analyses at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Observed Steady-state Volume of Distribution (Vss) of Elaprase | Week 3: Day 3-7 | 9.40 liters | Standard Deviation 3.464 |
| Idursulfase-IT 1 mg | Observed Steady-state Volume of Distribution (Vss) of Elaprase | Week 23: Day 3-7 | 13.19 liters | — |
Secondary
Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study. T1/2 is calculated by dividing 0.693 by Lambda z. Here, 0.693 is the natural logarithm of 2 and Lambda z is the first order rate constant.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idursulfase-IT 1 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA hours |
| Idursulfase-IT 1 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | NA hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 18.20 hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 15.57 hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 9.68 hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 22.43 hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 10.28 hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 14.21 hours |
| Idursulfase-IT 10 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 13.01 hours |
| Idursulfase-IT 30 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 15.52 hours |
| Idursulfase-IT 30 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 10.75 hours |
| Idursulfase-IT 30 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 14.16 hours |
| Idursulfase-IT 30 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 16.94 hours |
| Idursulfase-IT 30 mg | Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 10.28 hours |
Secondary
Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idursulfase-IT 1 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 8.03 hours |
| Idursulfase-IT 1 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 12.00 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 79 | 10.00 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | 24.03 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 12.00 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 9.99 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 43 | 12.00 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 55 | 12.00 hours |
| Idursulfase-IT 10 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 67 | 12.00 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | 36.07 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 43 | 10.02 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 12.00 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 67 | 12.00 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 24.00 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 55 | 7.97 hours |
| Idursulfase-IT 30 mg | Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 17.98 hours |
Secondary
Total Body Clearance (CL) of Elaprase
Time frame: 15 minutes prior to IV infusion, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 9, 11, and 24 hours during/after the IV infusion on Days 3-7 of Weeks 3 and 23
Population: Participants who received only Elaprase in HGT-HIT-045 and had evaluable samples were analyzed for this outcome measure. Number analyzed indicates the number of participants with data available for analyses at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Total Body Clearance (CL) of Elaprase | Week 3: Day 3-7 | 1.94 liters per hour (L/h) | Standard Deviation 1.677 |
| Idursulfase-IT 1 mg | Total Body Clearance (CL) of Elaprase | Week 23: Day 3-7 | 3.47 liters per hour (L/h) | — |
Secondary
Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA liters per hour (L/h) | — |
| Idursulfase-IT 1 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | NA liters per hour (L/h) | — |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 3.59 liters per hour (L/h) | Standard Deviation 0.763 |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 4.80 liters per hour (L/h) | Standard Deviation 2.667 |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 5.96 liters per hour (L/h) | Standard Deviation 2.207 |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 5.67 liters per hour (L/h) | — |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 4.33 liters per hour (L/h) | Standard Deviation 0.377 |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 6.33 liters per hour (L/h) | Standard Deviation 1.548 |
| Idursulfase-IT 10 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 6.10 liters per hour (L/h) | Standard Deviation 0.619 |
| Idursulfase-IT 30 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 9.46 liters per hour (L/h) | Standard Deviation 2.319 |
| Idursulfase-IT 30 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 8.25 liters per hour (L/h) | Standard Deviation 0.191 |
| Idursulfase-IT 30 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 6.29 liters per hour (L/h) | — |
| Idursulfase-IT 30 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 6.61 liters per hour (L/h) | Standard Deviation 3.295 |
| Idursulfase-IT 30 mg | Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (Cl/F) of Idursulfase-IT Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 6.92 liters per hour (L/h) | Standard Deviation 1.154 |
Secondary
Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase
Participants in 1 mg arm group were assessed for PK analysis in the HGT-HIT-045 study.
Time frame: 15 minutes prior to IT injection, at 1,2,3,4,6,8,12,24,30,36 hours (±1 hour) following IT injection on Day 2 of Weeks 3,23, for 1 mg arm group and on Day 2 of Weeks 3,23, Months 19,31,43,55,67,79 for 10 and 30 mg arm groups
Population: PK population included all participants who received study drug and participated in the scheduled pharmacokinetic studies, and for whom at least 1 post-dose PK blood sample was collected. Overall number analyzed indicates the number of participants with data available for analyses. Number analyzed indicates the number of participants with data available for analyses at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 3: Day 2 | NA liters | — |
| Idursulfase-IT 1 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 52.831 liters | — |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 94.18 liters | Standard Deviation 21.961 |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 116.91 liters | Standard Deviation 84.881 |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 79 | 79.22 liters | Standard Deviation 8.364 |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Week 23: Day 2 | 183.31 liters | — |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 68.06 liters | Standard Deviation 21.783 |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 130.84 liters | Standard Deviation 15.624 |
| Idursulfase-IT 10 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 115.31 liters | Standard Deviation 29.26 |
| Idursulfase-IT 30 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 67 | 206.92 liters | Standard Deviation 11.864 |
| Idursulfase-IT 30 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 55 | 127.77 liters | Standard Deviation 11.009 |
| Idursulfase-IT 30 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 31: Day 2 | 128.63 liters | — |
| Idursulfase-IT 30 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 19: Day 2 | 152.82 liters | Standard Deviation 45.153 |
| Idursulfase-IT 30 mg | Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of Dose Absorbed (Vz/F) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Month 43 | 104.93 liters | Standard Deviation 44.848 |
Secondary
Volume of Distribution (Vz) of Elaprase
Volume of distribution associated with the terminal slope (Vz) of Elaprase was assessed.
Time frame: 15 minutes prior to IV infusion and at multiple timepoints (0.5, 1, 1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours) following IV infusion on Days 3-7 of Weeks 3 and 23
Population: Participants who received only Elaprase in HGT-HIT-045 and had evaluable samples were analyzed for this outcome measure. Number analyzed indicates the number of participants with data available for analyses at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Idursulfase-IT 1 mg | Volume of Distribution (Vz) of Elaprase | Week 3: Day 3-7 | 19.91 liters | Standard Deviation 13.874 |
| Idursulfase-IT 1 mg | Volume of Distribution (Vz) of Elaprase | Week 23: Day 3-7 | 34.20 liters | — |