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®

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hunter Syndrome

Intervention / Treatment
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* Other: Control
* Drug: Idursulfase IT (1 mg)
* Drug: Idursulfase IT (10 mg)
* Drug: Idursulfase IT (30 mg)


Participation Criteria
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Eligibility Criteria
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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: 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. The patient has an IQ ≥78 The patient has a CNS shunt. 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. 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 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 or patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns. The patient has a history of poorly controlled seizure disorder. The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results. 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. The patient has received treatment with any investigational drug or device within the 30 days prior to study entry. 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 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. The patient has skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30 cm H2O(water) .

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control<br>Untreated Patients | Other: Control<br>* 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.<br>|
| Experimental: Idursulfase -IT (1 mg)<br>monthly using an intrathecal drug delivery device (IDDD) | Drug: Idursulfase IT (1 mg)<br>* 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.<br>|
| Experimental: Idursulfase-IT (10 mg)<br>monthly using an intrathecal drug delivery device (IDDD) | Drug: Idursulfase IT (10 mg)<br>* 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.<br>|
| Experimental: Idursulfase -IT (30 mg)<br>monthly using an intrathecal drug delivery device (IDDD) | Drug: Idursulfase IT (30 mg)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Serious Adverse Event (SAE) |  | 6 months | 
| Number of Treatment Emergent Adverse Event (AE) | ITT patient population | Baseline to week 23 | 
| Safety Changes in Cerebrospinal Fluid (CSF)- White Blood Cells (WBC) | 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. | 6 months | 
| Safety: Development of Anti-idursulfase Antibodies (CSF) | Reflects development of anti-idursulfase antibodies post baseline. | 6 months | 
| Safety: Development of Anti-idursulfase Antibodies (Serum) |  | 6 months | 
| Clinically Significant ECG Findings at Any Time During the Study. | Electrocardiogram (ECG) parameters included: heart rate, sinus rhythm, atrial/ventricular hypertrophy, PR, QRS, QT and QTc intervals. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in CSF Glycosaminoglycans [GAGs] at Week 27 | Percent Change from Baseline to Week 27 | Baseline to Week 27 | 
| Level of Idursulfase in the CSF Compartment Resulting From Monthly Idursulfase IT Administrations | 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) | Week 27 (end of study) | 
| Concentration of Idursulfase in Serum After Single Administration (Week 3) in Conjunction With Elaprase | Values below lower limit of quantitation (LLOQ) are listed as 0. | Weeks 3 | 
| Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase |  | Weeks 23 | 
| % Change From Baseline in Urinary GAG |  | Baseline to Week 27 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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