Study of Long Term Safety and Clinical Outcomes of Idursulfase IT and Elaprase Treatment in Pediatric Participants Who Have Completed Study HGT-HIT-094

Study Overview
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Brief Summary
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This extension study will allow participants that completed Study HGT-HIT-094 to continue receiving Elaprase treatment in conjunction with idursulfase IT or to continue receiving Elaprase treatment and begin concurrent IT treatment for those that did not receive idursulfase IT treatment in Study HGT-HIT-094.

Official Title
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An Open Label Extension of Study HGT-HIT-094 Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Idursulfase Administered in Conjunction With Elaprase® in 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: Participants must have completed Visit Week 52 assessments in Study HGT-HIT-094 (NCT02055118). 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 consent/assent, as relevant, must be obtained. The participant has continued to receive Elaprase on a regular basis in Study HGT-HIT-094 (NCT02055118). Exclusion Criteria: The participant has experienced, in the opinion of the investigator, a safety or medical issue that contraindicates treatment with idursulfase-IT, including, but not limited to, uncontrolled seizure disorder, bleeding disorder, and clinically relevant hypertension. The participant has a known hypersensitivity to any of the components of idursulfase-IT. The participant has clinically relevant intracranial hypertension. The participant is enrolled in another clinical study, other than HGT-HIT-094 (NCT02055118), that involves clinical investigations or use of any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to study enrollment or at any time during the study. The participant has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to compromised airways or other conditions. The participant has a condition that is contraindicated as described in the SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with Guidewire (SOPH-A-PORT Mini S) intrathecal drug delivery device (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 1 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.

Ages Eligible for Study
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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>Participants will receive 10 milligrams (mg) of idursulfase-IT intrathecally via intrathecal drug delivery device (IDDD) or lumbar puncture (LP) once every 28 days along with standard-of-care therapy with Elaprase for 480 weeks. Participants who are younger than 3 years of age will receive an adjusted dose of 7.5 mg (greater than [>] 8 months to 30 months of age) and 10 mg (>30 months to 3 years of age) of idursulfase-IT. | Drug: Idursulfase-IT<br>* Participants will receive 10 mg of idursulfase-IT intrathecally via IDDD or LP once every 28 days. Participants who are younger than 3 years of age will receive an adjusted dose of 7.5 mg (>8 months to 30 months of age) and 10 mg (>30 months to 3 years of age).<br>* Other names: HGT-2310;Drug: Elaprase<br>* Participants will receive intravenous (IV) Elaprase infusions at a minimum of 48 hours after IT administration of idursulfase-IT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An adverse event is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related. | From start of study drug administration up to 121 months | 
| Number of Participants With Clinically Significant Changes in Vital Signs, Laboratory Parameters, and 12-lead Electrocardiogram (ECG) Findings | Number of participants with clinically significant changes will be reported. | From start of study drug administration up to 121 months | 
| Maximum Observed Serum Concentration (Cmax) of Idursulfase | The Cmax of Idursulfase will be assessed. | Baseline through Month 121 | 
| Maximum Observed Concentration (Cmax) of Idursulfase in Cerebrospinal Fluid (CSF) | The Cmax of Idursulfase in CSF will be assessed. | Baseline through Month 121 | 
| Change From Baseline in the Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) | Concentration of GAG in CSF will be assessed. | Baseline through Month 121 | 
| Change From Baseline in the Concentration of Glycosaminoglycan (GAG) in Urine | Concentration of GAG in urine will be assessed. | Baseline through Month 121 | 
| Number of Participants who Report Anti-idursulfase Antibodies in Cerebrospinal Fluid (CSF) | The presence of idursulfase-specific antibodies will be assessed. | From start of study drug administration up to 121 months | 
| Number of Participants who Report Anti-idursulfase Antibodies in Serum | The presence of idursulfase-specific antibodies will be assessed. | From start of study drug administration up to 121 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) Standard Scores and Standard Cluster Scores | The DAS-II will be used to assess all participants of age 2 years, 6 months or older. The DAS-II comprises 2 overlapping batteries. The Early Years battery is designed for children ages 2 years, 6 months through 6 years, 11 months. The Early Years battery is further divided into the Lower Level for children ages 2 years, 6 months through 3 years, 5 months and Upper Level for children ages 3 years 6 months through 6 years, 11 months. The School Age Battery is designed for children ages 7 years, 0 months through 17 years, 11 months. These batteries are fully co-normed for ages 5 years, 0 months, through 8 years, 11 months. The cluster areas include general conceptual ability (GCA), Verbal, Nonverbal, Spatial, and Special Nonverbal Composite (SNC). The cluster area score represents a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. | Baseline through Month 121 | 
| Change From Baseline in Age Equivalent Scores of the Bayley Scales of Infant Development, Third Edition (BSID-III) Domains | Participants who are younger than 2 years, 6 months, will be assessed using the BSID-III. The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. Raw scores (range 40-160) will be converted to age- equivalent scores to measure ability, skill, and knowledge, expressed as the age at which most individuals reach the same level (age norm; range: 0, unbound). | Baseline through Month 121 | 
| Change From Baseline in Development Quotient (DQ) of the Bayley Scales of Infant Development, Third Edition (BSID-III) Domains | Participants who are younger than 2 years, 6 months, will be assessed using the BSID-III. The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which will be computed as a ratio and expressed as a percentage using the age equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0-100). | Baseline through Month 121 | 
| Change From Baseline in Standard Scores of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Domains | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behaviour composite (a composite of the other 4 domains). The standard scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. | Baseline through Month 121 | 
| Change From Baseline in Standard Composite Scores of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Domains | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The ABC score ranges from 20 to 160 on which higher scores indicate a higher level of adaptive functioning. A positive change value indicates improvement in adaptive functioning. | Baseline through Month 121 | 
| Change From Baseline in Age Equivalents Score of the Differential Ability Scales, Second Edition (DAS-II) | DAS-II will be used to assess all participants of age 2 years (Y), 6 months (M) or older. DAS-II comprises 2 overlapping batteries. Early Years Battery (EYB) is designed for ages 2Y,6M-6Y,11M. School Age Battery is designed for ages 7Y,0M-17Y,11M. These batteries are fully co-normed for age 5Y,0M-8Y,11M. Core subtests include Verbal (V) Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction (PC), Matrices (M) and Copying for DAS-II Early Y and Recall of Designs, Word Definitions, PC, M, Verbal Similarities, and Sequential and Quantitative Reasoning for DAS-II School Years. Standardized scores will be converted to age equivalent scores (AES) to measure ability, skill, and knowledge expressed as age at which most individuals reach same level. Mean AES will be obtained by averaging out AES. Higher score (HS) indicates greater cognitive ability (CA). Subtests score represent a score (mean=50 and standard deviation of 10) on which HS indicate a higher level of CA. | Baseline through Month 121 | 
| Change From Baseline in Developmental Quotients (DQ) of the Differential Ability Scales, Second Edition (DAS-II) | The DAS-II will be used to assess all participants of age 2 years (Y), 6 months (M) or older. The DAS-II comprises 2 overlapping batteries. The Early Years battery (EYB) is designed for children ages (CA) 2Y, 6M, through 6Y, 11M. The EYB is further divided into the Lower Level for CA 2Y, 6M through 3Y, 5M and Upper Level for CA 3Y, 6M through 6Y, 11M. The School Age Battery is designed for CA 7Y, 0M through 17Y, 1M. These batteries are fully co-normed for ages 5Y, 0M, through 8Y, 11M. The core subtests include Verbal Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, Matrices, and Copying for the DAS-II Early Y and Recall of Designs, Word Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential and Quantitative Reasoning for the DAS-II School Y. The DQ will be computed as a ratio and expressed as a percentage using the age equivalent score (AES) divided by the age at testing ([AES/chronological age] × 100; range, 0-100). | Baseline through Month 121 | 
| Change From Baseline in T-scores of the Core Subtests Differential Ability Scales, Second Edition (DAS-II) | The DAS-II will be used to assess all participants of age 2 years (Y), 6 months (M) or older. The DAS-II comprises 2 overlapping batteries. The Early Years battery (EYB) is designed for children ages (CA) 2Y, 6M, through 6Y, 11M. The EYB is further divided into the Lower Level for CA 2Y, 6M through 3Y, 5M and Upper Level for CA 3Y, 6M through 6Y, 11M. The School Age Battery is designed for CA 7Y, 0M through 17Y, 11M. These batteries are fully co-normed for ages 5Y, 0M, through 8Y, 11M. The core subtests (CS) include Verbal Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, Matrices, and Copying for the DAS-II Early Years and Recall of Designs, Word Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential and Quantitative Reasoning for the DAS-II School Years. The CS score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. | Baseline through Month 121 | 
| Change From Baseline in Age Equivalents Score of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Sub Domains | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following subdomains of 5 key domains: Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills), Motor Skills (Gross, Fine). The mean age equivalent score will be obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills (range: 0, unbound). | Baseline through Month 121 | 
| Change From Baseline in Developmental Quotients (DQ) of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Sub Domains | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following subdomains of 5 key domains: Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills), Motor Skills (Gross, Fine). The DQ will be computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range, 0-100). | Baseline through Month 121 | 
| Change From Baseline in v-Scores of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Sub Domains | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following subdomains of 5 key domains: Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills), Motor Skills (Gross, Fine). The V-scale scores represent a score (mean = 15 and standard deviation of 3; range: 1-24) on which higher scores indicate a higher level of adaptive functioning. | Baseline through Month 121 | 
| Change From Baseline in v-Scale Scores of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Maladaptive Behavior Index and its Subscales | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. Maladaptive behavior index is a composite of the internalizing, externalizing, and other types of undesirable behavior that may interfere with the individual's adaptive functioning. The v-Scale scores represent a score (mean = 15 and standard deviation of 3; range: 1-24) on which higher scores indicate a higher level of adaptive functioning. | Baseline through Month 121 | 
| Change From Baseline in Observed Maladaptive Levels of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Maladaptive Behavior Index and its Subscales | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. Maladaptive behavior index is a composite of the internalizing, externalizing, and other types of undesirable behavior that may interfere with the individual's adaptive functioning. The V scale scores represent a score (mean = 15 and standard deviation of 3; range: 1-24) on which higher scores indicate a higher level of cognitive ability. | Baseline through Month 121 | 
| Change From Baseline in Brain Structure Volume as Measured by Magnetic Resonance Imaging (MRI) | Brain structure volume will be assessed from brain total intracranial volume, brain total tissue volume, brain total white matter, brain total gray matter, and total CSF volume as measured by MRI. | Baseline through Month 121 |