Extension Study of HGT-HIT-045 Evaluating Long-Term Safety and Clinical Outcomes of Idursulfase-IT in Conjunction With Elaprase in Pediatric Participants With Hunter Syndrome and Cognitive Impairment

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label Extension of Study HGT-HIT-045 Evaluating Long-Term Safety and Clinical Outcomes of Intrathecal Idursulfase-IT Administered in Conjunction With Intravenous Elaprase® in Pediatric Patients With Hunter Syndrome and Cognitive Impairment

Conditions
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Hunter Syndrome

Intervention / Treatment
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* Drug: Idursulfase-IT
* Drug: Elaprase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have completed all study requirements and end of study assessments for study HGT-HIT-045 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 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: The participant has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device 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 The participant's drug therapy requires substances known to be incompatible with the materials of construction The participant has a known or suspected local or general infection The participant is at risk of abnormal bleeding due to a medical condition or therapy The participant has one or more spinal abnormalities that could complicate safe implantation or fixation The participant has a functioning CSF shunt device The participant has shown an intolerance to an implanted device The participant has an opening CSF pressure upon lumbar puncture that exceeds 30.0 centimeter (cm) water (H2O).

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idursulfase-IT<br>Idursulfase-IT will be administered once monthly and weekly IV infusions of Elaprase at the dose used in study HGT-HIT-045 via intrathecal drug delivery device (IDDD). | Drug: Idursulfase-IT<br>* Participants will receive Idursulfase-IT once monthly at the dose used in study HGT-HIT-045 via intrathecal drug delivery device (IDDD).<br>Drug: Elaprase<br>* Participants will receive weekly IV infusions of commercially available Elaprase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. Treatment-emergent AEs are 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). | From start of study drug administration up to follow-up (169 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| 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 | Area under the curve from the time of dosing to the last measureable concentration (AUC0-t) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Maximum Observed Concentration (Cmax) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| Time of Maximum Observed Concentration (tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase | Time of maximum observed concentration (tmax) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| 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 | Total body clearance for extravascular administration divided by the fraction of dose absorbed (Cl/F) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| 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 | Volume of distribution associated with the terminal slope following extravascular administration divided by the fraction of dose absorbed (Vz/F) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | First order rate constant (Lambda z) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase | Terminal half-life (t1/2) of idursulfase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Months 19, 31, and 43 | 
| Total Body Clearance (Cl) of Elaprase | Total body clearance (Cl) of Elaprase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Month 19 | 
| Volume of Distribution (Vz) of Elaprase | Volume of distribution associated with the terminal slope (Vz) of Elaprase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Month 19 | 
| Observed Steady-state Volume of Distribution (Vss) of Elaprase | Observed steady-state volume of distribution (Vss) of Elaprase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Month 19 | 
| Mean Residence Time (MRT) of Elaprase | Mean residence time (MRT) of Elaprase will be assessed. | 15 minutes prior to IT injection, 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours (h) following IT injection on Weeks 3 and 23, Day 2 of Month 19 | 
| Change From Baseline in CSF Biomarkers | Change from baseline in CSF biomarkers glycosaminoglycan (GAG [HS/DS]) will be assessed. | Baseline, Day 2 of Week 1, Day 2 Pre dose on Weeks 3, 7, 11, 15, 19, 23, 27, Months 7 - 169 | 
| Change From Baseline in Urinary Glycosaminoglycan (GAG) | Change from baseline in urinary GAG will be assessed. | Baseline, Day 1 Pre dose on Weeks 3, 7, 11, 15, 19, 23, 27, Months 7 - 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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