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 Description

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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.

Condition or disease	Intervention/treatment	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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	16 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Study Start Date :	November 2009
Actual Primary Completion Date :	October 2012
Actual Study Completion Date :	October 2012

Arms and Interventions

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Arm	Intervention/treatment
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.

Outcome Measures

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Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	3 Years to 18 Years (Child, Adult)
Sexes 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

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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

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Publications:

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.

Responsible Party:	Shire
ClinicalTrials.gov Identifier:	NCT00920647 History of Changes
Other Study ID Numbers:	HGT-HIT-045; 2010-020048-36 ( EudraCT Number )
First Posted:	June 15, 2009
Results First Posted:	May 16, 2014
Last Update Posted:	October 28, 2015
Last Verified:	April 2014

Keywords provided by Shire:

hunters syndrome; hunter's syndrome; hunter disease; hunters disease; hunter's disease; Mucopolysaccharidosis(MPS) II; 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:

Syndrome; Mucopolysaccharidosis II; Disease; Pathologic Processes; 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