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临床试验/NCT02055118
NCT02055118已完成2 期

A Controlled, Randomized, Two-arm, Open-label, Assessor-blinded, Multicenter Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment

Shire18 个研究点 分布在 7 个国家目标入组 58 人开始时间: 2014年3月24日最近更新:
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适应症

试验速览

阶段
2 期
状态
已完成
发起方
Shire
入组人数
58
试验地点
18
主要终点
Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Week 52
研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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.

详细描述

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.

研究设计

研究类型
Interventional
分配方式
Randomized
干预模型
Parallel
主要目的
Treatment
盲法
None

入排标准

年龄范围
— 至 18 Years（Child, Adult）
性别
Male
接受健康志愿者
否

入选标准

  • •Inclusion Criteria for the Pivotal Study
  • •Patients must meet all of the following criteria to be considered eligible for randomization in the pivotal study:
  • •The patient is male and is ≥3 and <18 years of age at the time of informed consent.
  • •(Patients who are younger than 3 years of age may be enrolled in a separate substudy provided that they meet other inclusion criteria, provided below.)
  • •The patient must have a documented diagnosis of MPS II.
  • •The patient has evidence at Screening of Hunter syndrome-related cognitive impairment defined as follows:
  • •A patient who is ≥3 and <13 years of age must have one of the following criteria (3a OR 3b):
  • •A GCA score ≥55 and ≤85 OR
  • •If the patient has a GCA score at Screening >85, there must be evidence of a decrease in GCA score of ≥10 points over 12 months from a previously documented test result in observational study HGT-HIT-
  • •A patient who is ≥13 and <18 years of age must have both of the following criteria (3c AND 3d):
  • •A GCA score of ≥55 and ≤
  • •There must be evidence of a decrease in GCA score of ≥10 points over 12 months from a previously documented
  • •The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
  • •The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the Investigator's judgment to complete the required protocol testing and must be compliant with wearing the hearing aid(s), if needed, on scheduled testing days.
  • •The patient's parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board/Independent Ethics Committee approved informed consent form after all relevant aspects of the study have been explained and discussed. Consent of the patient's parent(s) or legally authorized guardian(s) and the patient's assent, if applicable, must be obtained prior to the start of any study procedures.
  • •Inclusion Criteria for the Substudy
  • •Patients must meet all of the following criteria to be considered eligible for enrollment in the separate substudy:
  • •The patient is male and is <3 years of age at the time of informed consent.
  • •The patient must have a documented diagnosis of MPS II.
  • •The patient has evidence at Screening of Hunter syndrome-related cognitive impairment
  • •The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
  • •The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the Investigator's judgment to complete the required protocol testing and must be compliant with wearing the hearing aid(s), if needed, on scheduled testing days.
  • •The patient's parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board/Independent Ethics Committee approved informed consent form after all relevant aspects of the study have been explained and discussed. Consent of the patient's parent(s) or legally authorized guardian(s) must be obtained prior to the start of any study procedures.

排除标准

  • •Patients who meet any of the following criteria are not eligible to be randomized into the pivotal study or enrolled in the separate substudy:
  • •The patient has clinically significant non-Hunter syndrome-related CNS involvement (such as Fragile-X syndrome) which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
  • •The patient has a large chromosomal deletion or complex rearrangement that includes a deletion of the FMR1 and/or FMR2 genes.
  • •The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
  • •The patient has contra-indications for performance of lumbar puncture such as musculoskeletal/spinal abnormalities or risk of abnormal bleeding.
  • •The patient has a history of complications from previous lumbar punctures or technical challenges in conducting lumbar punctures such that the potential risks would exceed possible benefits for the patient.
  • •The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O.
  • •The patient has experienced infusion-related anaphylactoid event(s) or has evidence of consistent severe adverse events related to treatment with Elaprase which, in the Investigator's opinion, may pose an unnecessary risk to the patient.
  • •The patient has received a cord blood or bone marrow transplant at any time or has received blood product transfusions within 90 days prior to Screening.
  • •The patient has a history of poorly controlled seizure disorder.
  • •The patient is unable to comply with the protocol (eg, has significant hearing or vision impairment, a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, known clinically significant psychiatric/behavioral instability, is unable to return for safety evaluations, or is otherwise unlikely to complete the study), as determined by the Investigator.
  • •The patient is enrolled in another clinical study that involves clinical investigation 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 patient 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 patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU), including but not limited to the presence of a CSF shunt device in the patient.

结局指标

主要结局

Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Week 52

时间窗: 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.

次要结局

  • Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 52(Baseline, Week 52)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • Percentile Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population(Baseline up to Week 52)
  • Change From Baseline in the Concentration of Glycosaminoglycans (GAG) in Cerebrospinal Fluid (CSF) at Week 52(Baseline, Week 52)
  • 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)
  • 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)
  • Participant Response to Quality of Life EuroQol-5D (EQ-5D) Questionnaire at Week 52(Week 52)
  • Development Quotient (DQ) of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population(Baseline up to Week 52)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • Concentration of Idursulfase in Cerebrospinal Fluid (CSF)(Pre-dose on Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48)
  • 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)
  • Composite Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population(Baseline up to Week 52)
  • 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)
  • 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)
  • 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)
  • Chronological Age of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population(Baseline up to Week 52)
  • Age Equivalent Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population(Baseline up to Week 52)
  • Raw Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population(Baseline up to Week 52)

研究者

发起方
Shire
申办方类型
Industry
责任方
Sponsor

研究点 (18)

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