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
ClinicalTrials.gov Identifier:
NCT00920647
First received: June 12, 2009
Last updated: June 4, 2014
Last verified: April 2014
  Purpose

Elaprase (idursulfase), a large molecular protein, is not expected to cross the blood brain barrier at therapeutic levels when administered intravenously. A new 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
Other: Control
Drug: Idursulfase IT (1 mg)
Drug: Idursulfase IT (10 mg)
Drug: Idursulfase IT (30 mg)
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 Intrathecal Idursulfase-IT Administered in Conjunction With Intravenous Elaprase in Pediatric Patients With Hunter Syndrome and Cognitive Impairment

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Number of Serious Adverse Event (SAE) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Number of Treatment Emergent Adverse Event (AE) [ Time Frame: Baseline to week 23 ] [ Designated as safety issue: Yes ]
    ITT patient population

  • Safety Changes in Cerebrospinal Fluid (CSF)- White Blood Cells (WBC) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    White blood cell count in CSF was monitored throughout the study as a way of assessing any potential inflammation of the meninges induced by idursulfase-IT.

  • Safety: Development of Anti-idursulfase Antibodies (CSF) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Reflects development of anti-idursulfase antibodies post baseline.

  • Safety: Development of Anti-idursulfase Antibodies (Serum) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Clinically Significant ECG Findings at Any Time During the Study. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Electrocardiogram (ECG) parameters included: heart rate, sinus rhythm, atrial/ventricular hypertrophy, PR, QRS, QT and QTc intervals.


Secondary Outcome Measures:
  • Change From Baseline in CSF Glycosaminoglycans [GAGs] at Week 27 [ Time Frame: Baseline to Week 27 ] [ Designated as safety issue: No ]
    Percent Change from Baseline to Week 27

  • Level of Idursulfase in the CSF Compartment Resulting From Monthly Idursulfase IT Administrations [ Time Frame: Week 27 (end of study) ] [ Designated as safety issue: No ]
    Samples collected from patients treated at doses of 1 mg and 30 mg, as well as the control group, were below the lower limit of detection of the bioanalytical method (3.13 ng/mL)

  • Concentration of Idursulfase in Serum After Single Administration (Week 3) in Conjunction With Elaprase [ Time Frame: Weeks 3 ] [ Designated as safety issue: No ]
    Values below lower limit of quantitation (LLOQ) are listed as 0.

  • Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase [ Time Frame: Weeks 23 ] [ Designated as safety issue: No ]
  • % Change From Baseline in Urinary GAG [ Time Frame: Baseline to Week 27 ] [ Designated as safety issue: No ]

Enrollment: 16
Study Start Date: November 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
3 dose cohorts were planned. Within each dose cohort, patients will be randomized to 1 of 2 treatment options: treatment with study drug or no treatment with 4 treated patients per dose group and a total of 4 untreated patients (1-2 untreated patients will be assigned in each dose cohort). They will not undergo surgical placement of an Intrathecal Drug Delivery Device (IDDD), and will not receive Idursulfase-IT.
Experimental: Idursulfase -IT (1 mg)
monthly using an intrathecal drug delivery device (IDDD)
Drug: Idursulfase IT (1 mg)
The original design of the study was to test the dose levels of 10, 30 and 100 mg. This was based on a calculation of a minimally effective dose around 10 mg, with subsequent dose levels being chosen as increasing half-log steps. During the conduct of the study; however, it became clear that the 10 mg dose elicited a strong Pharmacodynamic response, as measured by a dramatic and sustained drop in the CSF GAG levels. This indicated the need to explore a lower level as a minimally effective dose level, leading to the introduction of the 1 mg group. Enrollment of patients in this dose cohort will commence after the last patient has been enrolled in 30 mg dose cohort. 4 patients will be undergo surgical placement of an IDDD and receive 1 mg idursulfase-IT as an IT injection via an IDDD once per month (ie, every 28 days) for 6 month.
Experimental: Idursulfase-IT (10 mg)
monthly using an intrathecal drug delivery device (IDDD)
Drug: Idursulfase IT (10 mg)
Patients will be enrolled in 10 mg dose cohort and 30 mg dose cohort in a sequential, escalating fashion. 4 patients will undergo surgical placement of an IDDD and receive 10 mg idursulfase-IT as an intrathecal (IT) injection via an IDDD once per month (ie, every 28 days) for 6 month.
Experimental: Idursulfase -IT (30 mg)
monthly using an intrathecal drug delivery device (IDDD)
Drug: Idursulfase IT (30 mg)
Patients will be enrolled in 10 mg dose cohort and 30 mg dose cohort in a sequential, escalating fashion. 4 patients will undergo surgical placement of an IDDD and receive 30 mg idursulfase-IT as an IT injection via an IDDD once per month (ie, every 28 days) for 6 month.

  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 H2O(water) .
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, United Kingdom
Sponsors and Collaborators
Shire
Investigators
Principal Investigator: Joseph Muenzer, MD, PhD University of North Carolina, Chapel Hill
  More Information

No publications provided

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00920647     History of Changes
Other Study ID Numbers: HGT-HIT-045, 2010-020048-36
Study First Received: June 12, 2009
Results First Received: October 31, 2013
Last Updated: June 4, 2014
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Shire:
hunters syndrome
hunter's syndrome
hunter disease
hunters disease
hunter's disease
iduronate 2 sulfatase
hunter syndrome treatment
hunter's syndrome treatment
hunter syndrome therapy
hunter's disease treatment
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
enzyme replacement therapy
mps society

Additional relevant MeSH terms:
Mucopolysaccharidosis II
Mental Retardation, X-Linked
Intellectual Disability
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 August 28, 2014