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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hunter Syndrome
• Intervention / Treatment: Drug: Idursulfase-IT; Drug: Elaprase

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • British Columbia Children's Hospital
• United Kingdom
  • Birmingham, United Kingdom, B46NH
    • Birmingham Children's Hospital
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H Lurie Childrens Hospital of Chicago
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Oregon
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9559
      • Vanderbilt Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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
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
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 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 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 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 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 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 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 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 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 Weeks 3 and 23
Volume of Distribution (Vz) of Elaprase	Volume of distribution associated with the terminal slope (Vz) of Elaprase will be assessed.	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 Weeks 3 and 23
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 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 Weeks 3 and 23
Mean Residence Time (MRT) of Elaprase	Mean residence time (MRT) of Elaprase will be assessed.	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 Weeks 3 and 23
Change From Baseline in Urinary Glycosaminoglycan (GAG)	Change from baseline in urinary GAG will be assessed.	Baseline, Day 1 Predose on Weeks 3, 7, 11, 15, 19, 23, 27, Months 7 - 169

Collaborators and Investigators

• Sponsor: Shire
• Investigators: Study Director: Shire Director, Takeda

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Genet Med. 2006 Sep;8(9):599. Wendt, Suzanne [corrected to Wendt, Susanne]; Puga, Antonio [corrected to Puga, Ana Cristina]; Conway, Ann Marie [corrected to Conway, Anne Marie].
• 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.

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2010
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: December 15, 2011
• First Submitted That Met QC Criteria: January 6, 2012
• First Posted (Estimated): January 9, 2012

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: enzyme replacement therapy; MPS II; lysosomal storage disorder; lysosomal storage disease; MPS 2; 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; hunter disease; idursulfase; hunter's syndrome treatment
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Disease; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Cognition Disorders; Mucopolysaccharidoses; Syndrome; Mucopolysaccharidosis II; Cognitive Dysfunction
• Other Study ID Numbers: HGT-HIT-046; 2011-000212-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes