A Safety and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous System Involvement and Are Receiving Treatment With Elaprase®

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier:
NCT00920647
First received: June 12, 2009
Last updated: December 6, 2012
Last verified: December 2012
  Purpose

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.

This Phase I/II study is designed to obtain necessary safety and exposure data, as well as secondary and exploratory outcome measures, to be interpreted and used in the design of subsequent clinical trials.


Condition Intervention Phase
Hunter Syndrome
Drug: Idursulfase-IT
Other: Control
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Randomized Safety and Ascending Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug Delivery Device (IDDD) in Pediatric Patients With Hunter Syndrome Who Demonstrate Evidence of Central Nervous System Involvement and Who Are Receiving Treatment With Elaprase

Resource links provided by NLM:


Further study details as provided by Shire Human Genetic Therapies, Inc.:

Primary Outcome Measures:
  • Safety assessed by adverse effects, changes in serum, urine and CSF chemistries, 12-lead electrocardiograms, and anti-idursulfase antibodies (in CSF and serum). [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Concentration of idursulfase in CSF and blood after single and repeated doses of intrathecal idursulfase-IT given in conjunction with Elaprase [ Time Frame: Weeks 3 and 23 ] [ Designated as safety issue: No ]
  • Change from baseline in CSF biomarkers (eg, glycosaminoglycans [GAGs] and GAG‑degradation products, heparan sulfate [HS]/dermatan sulfate [DS] oligosaccharides, and markers of lysosomal function) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change from baseline in urinary GAG and degradation byproducts by dose group and in comparison with untreated patients [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 16
Study Start Date: June 2009
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Control
Untreated Patients
Other: Control
Untreated patients will be enrolled (1-2 per dose cohort to a total of 4) and will not receive the IDDD or study drug. These patients will not undergo a second CSF sampling at Baseline but will undergo all end-of-study procedures 6 months after Baseline assessments are made.
Experimental: Idursulfase-IT
intrathecal, 1 mg, monthly
Drug: Idursulfase-IT
Four (4) patients will be randomized to receive 1 of 3 dose levels of idursulfase-IT (10, 30, or 100 mg) once a month via an IDDD. If the IT space is not accessible via the IDDD, idursulfase-IT may be administered via lumbar puncture up to 2 times during the first 4 treatment months.
Experimental: Idursulfase IT
intrathecal, 10 mg, monthly
Drug: Idursulfase-IT
Four (4) patients will be randomized to receive 1 of 3 dose levels of idursulfase-IT (10, 30, or 100 mg) once a month via an IDDD. If the IT space is not accessible via the IDDD, idursulfase-IT may be administered via lumbar puncture up to 2 times during the first 4 treatment months.
Experimental: Idursulfase -IT
intrathecal, 30 mg, monthly
Drug: Idursulfase-IT
Four (4) patients will be randomized to receive 1 of 3 dose levels of idursulfase-IT (10, 30, or 100 mg) once a month via an IDDD. If the IT space is not accessible via the IDDD, idursulfase-IT may be administered via lumbar puncture up to 2 times during the first 4 treatment months.

  Eligibility

Ages Eligible for Study:   3 Years to 18 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1a. A deficiency in iduronate-2-sulfatase enzyme activity of ≤10 % of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory) AND

1b. A documented mutation in the iduronate-2-sulfatase gene OR A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).

2. The patient is male and is ≥3 and <18 years of age .

3. The patient has evidence at Screening of early stage (duration and severity metrics per protocol) Hunter syndrome-related Central Nervous System (CNS) involvement, defined as:

  • The patient has an Intelligence quotient (IQ) ≤77 OR
  • There is evidence of a change of ≥1 but ≤2 standard deviations decline from a previous protocol-defined neurodevelopmental assessment. The duration of protocol-defined neurologic involvement is at least 3 months but less than 36 months as documented in the patient's medical history.

    4. The patient has received and tolerated a minimum of 6 months of treatment with weekly intravenous idursulfase, and has received 80% of the total planned infusions within that time frame, including having received 100% of the planned infusions within 4 weeks immediately preceding the surgical insertion of the IDDD.

    5. The patient must have sufficient auditory capacity, with or without aids, to complete the required protocol testing, and be compliant with wearing the aid on scheduled testing days.

    6. The patient, 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 with the patient. The guardians' consent must be obtained.

Exclusion Criteria:

  1. The patient has clinically significant non-Hunter syndrome-related CNS involvement which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
  2. The patient has an IQ ≥78
  3. The patient has a CNS shunt.
  4. The patient has experienced an infusion-related anaphylactoid event 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.
  5. 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
  6. 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.
  7. The patient or patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
  8. The patient has a history of poorly controlled seizure disorder.
  9. The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
  10. The patient is currently receiving chronic psychotropic therapy (e.g., neuroleptics, benzodiazepines, antidepressants, anticonvulsants, stimulants, etc.) which in the Investigator's opinion would likely affect the neurocognitive assessments. Intermittent use of selected short half-life agents (benzodiazepine, sedatives, etc.) may be permitted as long as there are 5 half-lives between last drug administered and study-related procedures including neurocognitive assessments.
  11. The patient has received treatment with any investigational drug or device within the 30 days prior to study entry.
  12. 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.
  13. The patient is unable to comply with the protocol, (e.g., 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.
  14. The patient has skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
  15. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30 cm (water)H2O.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00920647

Locations
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United Kingdom
Birmingham Children's Hospital
Birmingham, United Kingdom, B4 6NH
Sponsors and Collaborators
Shire Human Genetic Therapies, Inc.
Investigators
Principal Investigator: Joseph Muenzer, MD, PhD University of North Carolina, Chapel Hill
  More Information

Publications:
Responsible Party: Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier: NCT00920647     History of Changes
Other Study ID Numbers: HGT-HIT-045
Study First Received: June 12, 2009
Last Updated: December 6, 2012
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Shire Human Genetic Therapies, Inc.:
hunters syndrome
hunter's syndrome
hunter disease
hunters disease
hunter's disease
Mucopolysaccharidosis(MPS) II
Mucopolysaccharidosis(MPS)2
Mucopolysaccharidosis (MPS) 2
Mucopolysaccharidosis (mps) 2
Mucopolysaccharidosis (mps) ii
mucopolysaccharides
lysosomal storage disease
lysosomal storage disorder
chronic ear infection
enlarged adenoids
mps symptoms
mps diagnosis
ert treatment
elaprase
idursulfase
iduronate sulfatase
iduronate 2 sulfatase
enzyme replacement therapy
hunter syndrome treatment
hunter's syndrome treatment
hunter syndrome therapy
hunter's disease treatment
mps society

Additional relevant MeSH terms:
Mucopolysaccharidosis II
Mental Retardation, X-Linked
Mental Retardation
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

ClinicalTrials.gov processed this record on April 16, 2014