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

• ClinicalTrials.gov Identifier: NCT01506141
• Recruitment Status: Active, not recruiting
• First Posted: January 9, 2012
• Last Update Posted: April 27, 2022
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hunter Syndrome	Drug: Idursulfase-IT; Drug: Elaprase	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 1, 2010
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 31, 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to follow-up (169 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. 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).

Secondary Outcome Measures :

1. Area Under the Curve Extrapolated to Infinity (AUC0-infinity) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase [ Time Frame: 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 extrapolated to infinity, calculated using the observed value of the last non-zero concentration (AUC0-infinity) of idursulfase will be assessed.
2. 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 [ Time Frame: 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 will be assessed.
3. Maximum Observed Concentration (Cmax) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase [ Time Frame: 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 will be assessed.
4. Time of Maximum Observed Concentration (tmax) of Idursulfase Administered in as Intrathecal and in Conjunction With Elaprase [ Time Frame: 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 will be assessed.
5. 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 [ Time Frame: 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 will be assessed.
6. 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 [ Time Frame: 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 will be assessed.
7. First Order Rate Constant (Lambda z) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase [ Time Frame: 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 will be assessed.
8. Terminal Half-life (t1/2) of Idursulfase Administered as Intrathecal and in Conjunction With Elaprase [ Time Frame: 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 will be assessed.
9. Total Body Clearance (Cl) of Elaprase [ Time Frame: 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 ]
   Total body clearance (Cl) of Elaprase will be assessed.
10. Volume of Distribution (Vz) of Elaprase [ Time Frame: 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 associated with the terminal slope (Vz) of Elaprase will be assessed.
11. Observed Steady-state Volume of Distribution (Vss) of Elaprase [ Time Frame: 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 will be assessed.
12. Mean Residence Time (MRT) of Elaprase [ Time Frame: 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 will be assessed.
13. Change From Baseline in CSF Biomarkers [ Time Frame: 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 CSF biomarkers glycosaminoglycan (GAG [HS/DS]) will be assessed.
14. Change From Baseline in Urinary Glycosaminoglycan (GAG) [ Time Frame: Baseline, Day 1 Pre dose on Weeks 3, 7, 11, 15, 19, 23, 27, Months 7 - 169 ]
    Change from baseline in urinary GAG will be assessed.

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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:

  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
• The participant has an opening CSF pressure upon lumbar puncture that exceeds 30.0 centimeter (cm) water (H2O).

Contacts and Locations

Locations

United States, Illinois

Ann & Robert H Lurie Childrens Hospital of Chicago

Chicago, Illinois, United States, 60611

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Oregon

Legacy Emanuel Hospital

Portland, Oregon, United States, 97227

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Vanderbilt Children's Hospital

Nashville, Tennessee, United States, 37232-9559

United States, Utah

University of Utah Hospital

Salt Lake City, Utah, United States, 84132

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Canada, British Columbia

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

United Kingdom

Birmingham Children's Hospital

Birmingham, United Kingdom, B46NH

Sponsors and Collaborators

Shire

Investigators

• Study Director: Shire Physician; Shire

More Information

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].

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01506141
• Other Study ID Numbers: HGT-HIT-046; 2011-000212-25 ( EudraCT Number )
• First Posted: January 9, 2012
• Last Update Posted: April 27, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• 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.
• URL: https://vivli.org/ourmember/takeda/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Shire ):

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

Additional relevant MeSH terms:

Mucopolysaccharidosis II; Syndrome; Cognitive Dysfunction; Disease; Pathologic Processes; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases