Clinical trial NCT00920647: 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®
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hunter Syndrome
Keywords: enlarged adenoids
hunters syndrome
enzyme replacement therapy
hunter's syndrome
mps society
Mucopolysaccharidosis (mps) 2
mps diagnosis
hunter disease
iduronate 2 sulfatase
idursulfase
hunters disease
hunter's syndrome treatment
mucopolysaccharides
hunter syndrome treatment
Mucopolysaccharidosis (mps) ii
elaprase
hunter syndrome therapy
lysosomal storage disease
hunter's disease
Mucopolysaccharidosis(MPS) II
Mucopolysaccharidosis(MPS)2
hunter's disease treatment
lysosomal storage disorder
chronic ear infection
mps symptoms
iduronate sulfatase
ert treatment
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-06-15
Enrollment: 16
Sex: MALE
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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) .

Primary outcomes:
measure: Number of Serious Adverse Event (SAE)
timeFrame: 6 months
measure: Number of Treatment Emergent Adverse Event (AE)
timeFrame: Baseline to week 23
measure: Safety Changes in Cerebrospinal Fluid (CSF)- White Blood Cells (WBC)
timeFrame: 6 months
measure: Safety: Development of Anti-idursulfase Antibodies (CSF)
timeFrame: 6 months
measure: Safety: Development of Anti-idursulfase Antibodies (Serum)
timeFrame: 6 months
measure: Clinically Significant ECG Findings at Any Time During the Study.
timeFrame: 6 months
Secondary outcomes:
measure: Change From Baseline in CSF Glycosaminoglycans [GAGs] at Week 27
timeFrame: Baseline to Week 27
measure: Level of Idursulfase in the CSF Compartment Resulting From Monthly Idursulfase IT Administrations
timeFrame: Week 27 (end of study)
measure: Concentration of Idursulfase in Serum After Single Administration (Week 3) in Conjunction With Elaprase
timeFrame: Weeks 3
measure: Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase
timeFrame: Weeks 23
measure: % Change From Baseline in Urinary GAG
timeFrame: Baseline to Week 27
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Muenzer J, Hendriksz CJ, Fan Z, Vijayaraghavan S, Perry V, Santra S, Solanki GA, Mascelli MA, Pan L, Wang N, Sciarappa K, Barbier AJ. A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet Med. 2016 Jan;18(1):73-81. doi: 10.1038/gim.2015.36. Epub 2015 Apr 2.