Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment
- Conditions
- Hunter Syndrome
- Interventions
- Biological: idursulfase-ITOther: No IT treatment
- Registration Number
- NCT02055118
- Lead Sponsor
- Shire
- Brief Summary
Study HGT-HIT-094 is a multicenter study designed to determine the effect on clinical parameters of neurodevelopmental status of monthly IT administration of idursulfase-IT 10 mg for 12 months in pediatric patients with Hunter syndrome and cognitive impairment who have previously received and tolerated a minimum of 4 months of therapy with Elaprase.
- Detailed Description
Elaprase, a large molecular protein, is not expected to cross the blood brain barrier when administered intravenously. A revised formulation of idursulfase, idursulfase-IT, that differs from that of the intravenous (IV) formulation, Elaprase, has been developed to be suitable for delivery into the cerebrospinal fluid (CSF) via intrathecal administration.
Mucopolysaccharidosis II (MPS II) is a rare, X-linked, inherited disease that affects males nearly exclusively. The disease is caused by the absence of, or deficiency in, the activity of the lysosomal enzyme, iduronate-2-sulfatase (I2S) which acts to cleave O-linked sulfate moieties from the glycosaminoglycan (GAG) molecules dermatan sulfate and heparan sulfate.
Study HGT-HIT-094 is a controlled, randomized, two-arm, open-label, assessor-blinded, multicenter study to determine the effect on clinical parameters of neurodevelopmental status of monthly IT administration of idursulfase-IT 10 mg for 12 months in pediatric patients with Hunter syndrome and cognitive impairment who have previously received and tolerated a minimum of 4 months of therapy with Elaprase.
Pediatric patients under 3 years of age will be enrolled into a separate substudy to evaluate the safety and efficacy of idursulfase-IT. The separate substudy is open label and single arm. Patients who are enrolled in the substudy will receive idursulfase-IT treatment and follow the same schedule of study visits.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 58
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description idursulfase-IT idursulfase-IT 10 mg administered via IT using IDDD (intrathecal drug delivery device) once a month for 52 weeks. Nontreatment control No IT treatment Patients will receive weekly standard of care treatment with IV Elaprase only.
- Primary Outcome Measures
Name Time Method Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Week 52 Baseline, Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The GCA standard score of the DAS-II was used to obtain a general measure of cognitive ability. The GCA score represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. The score ranges from 30 to 170. A positive change value indicates improvement in cognitive ability.
- Secondary Outcome Measures
Name Time Method Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 52 Baseline, Week 52 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.
Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Weeks 16, 28 and 40 Baseline, Week 16, Week 28 and Week 40 The DAS-II was used to assess cognitive development in all randomized participants. The GCA standard score of the DAS-II was used to obtain a general measure of cognitive ability. The GCA score represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. The score ranges from 30 to 170. A positive change value indicates improvement in cognitive ability.
Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 16, 28 and 40 Baseline, Week 16, Week 28 and Week 40 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.
Change From Baseline of Development Quotients for Early Years of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The early years battery is designed for children ages 2 years 6 months through 6 years 11 months. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was 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). The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability.
Change From Baseline in Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Standard Scores of Other Domains at Weeks 16, 28, 40, 52 Baseline, Week 16, Week 28, Week 40 and Week 52 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 standard scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning. Communication, daily living skills, socialization and motor skills domains were reported here. The range for individual standard scores is 20-160.
Change From Baseline of Age Equivalent Score for Early Years of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The early years battery is designed for children ages 2 years 6 months through 6 years 11 months. Standardized scores were converted to age equivalent scores to measure ability, skill, and knowledge expressed as the age at which most individuals reach the same level. The mean age equivalent score is obtained by averaging out the age-equivalent scores. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability.
Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (CL/F) of Idursulfase After IT Administration Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48 The CL/F of idursulfase after IT administration was reported.
Percentile Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population Baseline up to Week 52 Participants who were younger than 3 years were 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. Percentile scores range from 1 to 99 with 50 as the mean and median. Higher percentile means higher the rank of the child relative to the normed population. Participant wise data at evaluable timepoints was reported for this outcome.
Change From Baseline of T-scores for Early Years of Core Subtests of the Differential Ability Scale, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The early years battery is designed for children ages 2 years 6 months through 6 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability.
Observed Maladaptive Levels of Maladaptive Behavior Index and Its Sub-scales of Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Baseline, Week 16, Week 28, Week 40 and Week 52 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 (MBI) 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 greater maladaptive behaviors. The v-scale score ranges for MBI, externalizing and internalizing scores are defined as clinically significant: 21-24, elevated: 18-20, average: 1-17.
Change From Baseline in the Concentration of Glycosaminoglycans (GAG) in Cerebrospinal Fluid (CSF) at Week 52 Baseline, Week 52 Change from baseline in the concentration of GAG in CSF was reported.
Participant Response to Quality of Life EuroQol-5D (EQ-5D) Questionnaire at Week 52 Week 52 The EQ-5D provides a descriptive profile and index value for health status. The questionnaire measures 5 dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, there are 5 levels of response: no problems, slight problems, moderate problems, severe problems, and unable to do/extreme problems.
Development Quotient (DQ) of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population Baseline up to Week 52 Participants who were younger than 3 years were 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). Higher values present better outcomes. Participant wise data at evaluable timepoints was reported for this outcome.
Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) Cluster Standard Scores at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The cluster scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability in each cluster: verbal (score range: 31-169), nonverbal (score range: 31-166) and spatial (score range: 32-170).
Change From Baseline of Age Equivalents for School Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The school age battery is designed for children ages 7 years 0 months through 17 years 11 months. Standardized scores were converted to age equivalent scores to measure ability, skill, and knowledge expressed as the age at which most individuals reach the same level. The mean age equivalent score is obtained by averaging out the age-equivalent scores. The higher score indicates greater cognitive ability. The subtest score represents a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, SQR stands for "Sequential \& Quantitative Reasoning".
Change From Baseline of Development Quotients of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was 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). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age equivalent scores for the all the sub-domains except for Gross and Fine motor skills. 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). A positive value indicates improvement in health and cognition.
Change From Baseline of V-Scale Scores of Maladaptive Behavior Index and Its Sub-scales at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 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 greater maladaptive behaviors. A positive change value indicates increase of maladaptive behavior.
Change From Baseline of Development Quotients for School Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The school age battery is designed for children ages 7 years 0 months through 17 years 11 months. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was 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). The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, SQR stands for "Sequential \& Quantitative Reasoning".
Change From Baseline of Age Equivalents Scores of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. Standardized scores (range 40-160) were converted to age equivalent scores to measure ability, skill, and knowledge expressed as the age at which most individuals reach the same level. The mean age equivalent score is obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills (range: 0, unbound). A positive value indicates improvement in health and cognition.
Maximum Observed Drug Concentration (Cmax) of Idursulfase After IT Administration Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48 The Cmax of idursulfase after IT administration was reported.
Area Under the Concentration Versus Time Curve From Zero From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of Idursulfase After IT Administration Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48 The AUC0-t of idursulfase after IT administration was reported.
Terminal Half-life (t1/2) of Idursulfase After IT Administration Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48 The t1/2 of idursulfase after IT administration was reported.
Concentration of Idursulfase in Cerebrospinal Fluid (CSF) Pre-dose on Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 CSF samples were collected via the IDDD or lumbar puncture prior to the injection of Idursulfase-IT.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Intrathecal Drug Delivery Device (IDDD)-Related Adverse Events From start of study treatment up to Week 53 An adverse event (AE) was 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. Treatment-emergent AEs for the no IT treatment group were defined as all AEs occurring on or after the date of randomization and at or before the end of the study (EOS) visit. Treatment-emergent AEs for the IT treatment group were defined as all AEs occurring on or after the date of the first IDDD implant surgery or Treatment-Emergentfirst dose of the investigational product (whichever was earlier) and at or before the EOS visit (+30 days) or 2 weeks after the removal of the last IDDD (whichever was later).
Composite Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population Baseline up to Week 52 Participants who were younger than 3 years were 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 composite score for the cognitive scale, language scale, and motor scale are normed and have a mean=100, SD=15 and range of 40-160. Higher values denote stronger skills and abilities in the domain, indicating better outcomes. Participant wise data at evaluable timepoints was reported for this outcome.
Change From Baseline of T-scores for School Age of Core Subtests of the Differential Ability Scale, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 The DAS-II was used to assess cognitive development in all randomized participants. The school age battery is designed for children ages 7 years 0 months through 17 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, SQR stands for "Sequential \& Quantitative Reasoning".
Change From Baseline of V-Scale Scores of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52 Baseline, Week 16, Week 28, Week 40 and Week 52 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 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. A positive change value indicates improvement in adaptive functioning.
Time to Reach Maximum Drug Concentration (Tmax) of Idursulfase After IT Administration Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48 The tmax of idursulfase after IT administration was reported.
Chronological Age of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population Baseline up to Week 52 Participants who were younger than 3 years were 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. Chronological age of the participants when assessed by the BSID-III scale was reported. Range 16.59 - 45.21 months. Participant wise data at evaluable timepoints was reported for this outcome.
Age Equivalent Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population Baseline up to Week 52 Participants who were younger than 3 years were 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. Standardized scores (range 40-160) were 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). Higher values present better outcomes. Participant wise data at evaluable timepoints was reported for this outcome.
Raw Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population Baseline up to Week 52 Participants who were younger than 3 years were 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 are converted to scaled scores that are based on normed populations. Raw score ranges: Cognitive scale 0-91, Receptive communication 0-49, Expressive communication 0-48, Fine motor 0-66 and Gross motor 0-72. Higher values indicate better outcomes. Participant wise data at evaluable timepoints was reported for this outcome.
Trial Locations
- Locations (9)
Instituto Nacional de Pediatría
🇲🇽Coyoacan, Ciudad De México, Mexico
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Hospital Infantil Universitario Niño Jesus
🇪🇸Madrid, Spain
Hôpital Femme Mère Enfant
🇫🇷Bron, France
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Children's Hospital and Research Center at Oakland
🇺🇸Oakland, California, United States
Ann & Robert H Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Women's and Children's Hospital, 72 King William Road
🇦🇺North Adelaide, Australia