Clinical trial NCT02055118: Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hunter Syndrome
Keywords: hunters disease
MPS II
lysosomal storage disorder
hunters syndrome
ert treatment
hunter's disease
iduronate sulfatase
MPS society
mps 2
enlarged adenoids
hunter's syndrome
iduronate 2 sulfatase
chronic ear infection
mucopolysaccharides
hunter syndrome therapy
hunter's syndrome treatment
enzyme replacement therapy
hunter syndrome treatment
elaprase
MPSII
lysosomal storage disease
mps diagnosis
mps symptoms
idursulfase
hunter disease
hunter's disease treatment
MPS2
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-02-04
Enrollment: 58
Sex: MALE
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria Inclusion Criteria for the Pivotal Study

Patients must meet all of the following criteria to be considered eligible for randomization in the pivotal study:

1. 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.)
2. The patient must have a documented diagnosis of MPS II.
3. 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):
   1. A GCA score ≥55 and ≤85 OR
   2. 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-090.

      A patient who is ≥13 and \<18 years of age must have both of the following criteria (3c AND 3d):
   3. A GCA score of ≥55 and ≤85. AND
   4. There must be evidence of a decrease in GCA score of ≥10 points over 12 months from a previously documented
4. The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
5. 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.
6. 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:

1. The patient is male and is \<3 years of age at the time of informed consent.
2. The patient must have a documented diagnosis of MPS II.
3. The patient has evidence at Screening of Hunter syndrome-related cognitive impairment
4. The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
5. 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.
6. 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.

Exclusion Criteria

Patients who meet any of the following criteria are not eligible to be randomized into the pivotal study or enrolled in the separate substudy:

1. 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.
2. The patient has a large chromosomal deletion or complex rearrangement that includes a deletion of the FMR1 and/or FMR2 genes.
3. The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
4. The patient has contra-indications for performance of lumbar puncture such as musculoskeletal/spinal abnormalities or risk of abnormal bleeding.
5. 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.
6. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O.
7. 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.
8. 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.
9. The patient has a history of poorly controlled seizure disorder.
10. 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.
11. 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.
12. 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.
13. 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.

Primary outcomes:
measure: Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Week 52
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Weeks 16, 28 and 40
timeFrame: Baseline, Week 16, Week 28 and Week 40
measure: Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 16, 28 and 40
timeFrame: Baseline, Week 16, Week 28 and Week 40
measure: Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) Cluster Standard Scores at Weeks 16, 28, 40 and 52
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: Change From Baseline in Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Standard Scores of Other Domains at Weeks 16, 28, 40, 52
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: 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
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: Change From Baseline of V-Scale Scores of Maladaptive Behavior Index and Its Sub-scales at Weeks 16, 28, 40 and 52
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: Observed Maladaptive Levels of Maladaptive Behavior Index and Its Sub-scales of Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
timeFrame: Baseline, Week 16, Week 28, Week 40 and Week 52
measure: Maximum Observed Drug Concentration (Cmax) of Idursulfase After IT Administration
timeFrame: Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
measure: Time to Reach Maximum Drug Concentration (Tmax) of Idursulfase After IT Administration
timeFrame: Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
measure: 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
timeFrame: Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
measure: Terminal Half-life (t1/2) of Idursulfase After IT Administration
timeFrame: Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
measure: Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (CL/F) of Idursulfase After IT Administration
timeFrame: Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
measure: Change From Baseline in the Concentration of Glycosaminoglycans (GAG) in Cerebrospinal Fluid (CSF) at Week 52
timeFrame: Baseline, Week 52
measure: Concentration of Idursulfase in Cerebrospinal Fluid (CSF)
timeFrame: Pre-dose on Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
measure: Participant Response to Quality of Life EuroQol-5D (EQ-5D) Questionnaire at Week 52
timeFrame: Week 52
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Intrathecal Drug Delivery Device (IDDD)-Related Adverse Events
timeFrame: From start of study treatment up to Week 53
measure: Composite Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population
timeFrame: Baseline up to Week 52
measure: Percentile Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population
timeFrame: Baseline up to Week 52
measure: Age Equivalent Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population
timeFrame: Baseline up to Week 52
measure: Chronological Age of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population
timeFrame: Baseline up to Week 52
measure: Development Quotient (DQ) of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population
timeFrame: Baseline up to Week 52
measure: Raw Scores of Bayley Scales of Infant Development (BSID-III) Scale in Substudy Population
timeFrame: Baseline up to Week 52
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Chicago
country: United States
facility: Ann & Robert H Lurie Children's Hospital of Chicago
state: Illinois
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: North Adelaide
country: Australia
facility: Women's and Children's Hospital, 72 King William Road
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Bron
country: France
facility: Hôpital Femme Mère Enfant
city: Coyoacan
country: Mexico
facility: Instituto Nacional de Pediatría
state: Ciudad De México
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Muenzer J, Burton BK, Harmatz P, Gutierrez-Solana LG, Ruiz-Garcia M, Jones SA, Guffon N, Inbar-Feigenberg M, Bratkovic D, Hale M, Wu Y, Yee KS, Whiteman DAH, Alexanderian D; HGT-HIT-094 Study Group. Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study. Mol Genet Metab. 2022 Sep-Oct;137(1-2):127-139. doi: 10.1016/j.ymgme.2022.07.017. Epub 2022 Aug 2.
citation: Muenzer J, Burton BK, Harmatz P, Gutierrez-Solana LG, Ruiz-Garcia M, Jones SA, Guffon N, Inbar-Feigenberg M, Bratkovic D, Hale M, Wu Y, Yee KS, Whiteman DAH, Alexanderian D; SHP609-302 study group. Long-term open-label extension study of the safety and efficacy of intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II. Mol Genet Metab. 2022 Sep-Oct;137(1-2):92-103. doi: 10.1016/j.ymgme.2022.07.016. Epub 2022 Aug 2.