An 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

• Idursulfase-IT (Drug): Idursulfase-IT once monthly via IDDD.
• Elaprase (Drug): Weekly IV infusions of commercially available Elaprase.

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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]
• 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.

Sex: Male, ages: 3 Years to 18 Years

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).

Participant flow

Outcome results

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: Idursulfase-IT 1 mg 4; Idursulfase-IT 10 mg 10; Idursulfase-IT 30 mg 5
• Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in Laboratory Parameters (Primary), Count of participants, Participants: Idursulfase-IT 1 mg 0; Idursulfase-IT 10 mg 0; Idursulfase-IT 30 mg 0
• Number of Participants With Clinically Significant Changes or Apparent Difference Across Treatment Groups in 12-lead Electrocardiogram (ECG) Findings (Primary), Count of participants, Participants: Idursulfase-IT 1 mg 0; Idursulfase-IT 10 mg 0; Idursulfase-IT 30 mg 0
• CSF Chemistries: Change From Baseline in CSF Total Cell Count (Primary), Mean, 10^6 cells/Liter (L): Idursulfase-IT 1 mg 1.0 +/- 0.00; Idursulfase-IT 10 mg 1.0 +/- 0.00; Idursulfase-IT 30 mg 1.0 +/- 0.00
• CSF Chemistries: Change From Baseline in CSF Glucose (Primary), Mean, millimoles per liter (mmol/L): Idursulfase-IT 1 mg 2.950 +/- 0.265; Idursulfase-IT 10 mg 2.850 +/- 0.217; Idursulfase-IT 30 mg 3.000 +/- 0.200
• CSF Chemistries: Change From Baseline in CSF Protein (Primary), Mean, grams per liter (g/L): Idursulfase-IT 1 mg 0.400 +/- 0.194; Idursulfase-IT 10 mg 0.282 +/- 0.144; Idursulfase-IT 30 mg 0.530 +/- 0.368
• Number of Participants With Anti-idursulfase Antibodies in CSF (Primary), Count of participants, Participants: Idursulfase-IT 1 mg 3; Idursulfase-IT 10 mg 1; Idursulfase-IT 30 mg 1
• Number of Participants With Anti-idursulfase Antibodies in Serum (Primary), Count of participants, Participants: Idursulfase-IT 1 mg 3; Idursulfase-IT 10 mg 2; Idursulfase-IT 30 mg 2
• Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase (Secondary), Mean, hours*nanograms per milliliter(h*ng/mL): Idursulfase-IT 1 mg NA +/- NA; Idursulfase-IT 10 mg ; 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 (Secondary), Mean, h*ng/mL: Idursulfase-IT 1 mg NA +/- NA; Idursulfase-IT 10 mg 1214 +/- NA; Idursulfase-IT 30 mg 3746 +/- NA
• Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase (Secondary), Mean, nanograms per milliliter (ng/mL): Idursulfase-IT 1 mg NA +/- NA; Idursulfase-IT 10 mg 43.95 +/- NA; Idursulfase-IT 30 mg 146.75 +/- NA
• Time of Maximum Observed Concentration (Tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase (Secondary), Median, hours: Idursulfase-IT 1 mg NA (NA to NA); Idursulfase-IT 10 mg 24.03 (NA to NA); Idursulfase-IT 30 mg 36.07 (NA to NA)
• 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 (Secondary), Mean, liters per hour (L/h): Idursulfase-IT 1 mg NA +/- NA; Idursulfase-IT 10 mg ; 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 (Secondary), Mean, liters: Idursulfase-IT 1 mg NA +/- NA; Idursulfase-IT 10 mg ; Idursulfase-IT 30 mg
• First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase (Secondary), Mean, per hour (/h): Idursulfase-IT 1 mg NA +/- NA; Idursulfase-IT 10 mg ; Idursulfase-IT 30 mg
• Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase (Secondary), Median, hours: Idursulfase-IT 1 mg NA (NA to NA); Idursulfase-IT 10 mg ; Idursulfase-IT 30 mg
• Total Body Clearance (CL) of Elaprase (Secondary), Mean, liters per hour (L/h): Elaprase IV Infusion 0.5 mg/kg 1.94 +/- 1.677
• Observed Steady-state Volume of Distribution (Vss) of Elaprase (Secondary), Mean, liters: Elaprase IV Infusion 0.5 mg/kg 9.40 +/- 3.464
• Volume of Distribution (Vz) of Elaprase (Secondary), Mean, liters: Elaprase IV Infusion 0.5 mg/kg 19.91 +/- 13.874
• Mean Residence Time Extrapolated to Infinity (MRT0-inf) of Elaprase (Secondary), Mean, hours: Elaprase IV Infusion 0.5 mg/kg 6.49 +/- 3.817
• 2 more outcome measures not shown.

Adverse events

Time frame: From start of study drug administration up to follow-up (up to 165 months)

Serious adverse events by term

8 more terms not shown.

Other adverse events by term

474 more terms not shown.

• Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. 2007 Mar;90(3):329-37. doi: 10.1016/j.ymgme.2006.09.001. Epub 2006 Dec 20. PMID 17185020
• Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M, Vijayaraghavan S, Wendt S, Puga AC, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura A. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006 Aug;8(8):465-73. doi: 10.1097/01.gim.0000232477.37660.fb. PMID 16912578
• Results publication: Muenzer J, Vijayaraghavan S, Stein M, Kearney S, Wu Y, Alexanderian D. Long-term open-label phase I/II extension study of intrathecal idursulfase-IT in the treatment of neuronopathic mucopolysaccharidosis II. Genet Med. 2022 Jul;24(7):1437-1448. doi: 10.1016/j.gim.2022.04.002. Epub 2022 May 20. PMID 35588317

• Study Protocol (PDF, 2021-08-17)
• Statistical Analysis Plan (PDF, 2023-02-21)

• Study Director, Study director, Takeda