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Hunter SyndromePhase 1/2NCT00920647

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®

A Phase 1/2 study testing Idursulfase IT (1 mg), Idursulfase IT (10 mg) and Idursulfase IT (30 mg) in people with Hunter Syndrome, run by Shire at 3 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 3 to 18 years, men only
Conditions the study is for
Hunter Syndrome
What is being tested?
Idursulfase IT (1 mg), Idursulfase IT (10 mg) and Idursulfase IT (30 mg)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
3 sitesin 2 countries
Study dates
18 Nov 2009to 29 Oct 2012
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 to 18 years
  • Men only
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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) .

Trial locations and contacts

3 sites in 2 countries.

3 sites in 2 countries

United Kingdom2 sites

  • Birmingham Children's Hospital

    Birmingham, B4 6NH

  • Birmingham Children's Hospital NHS Foundation Trust

    Birmingham

Other trials in United Kingdom

United States1 site

  • University of North Carolina at Chapel Hill

    Chapel Hill, North Carolina, 27599

Other trials in United States

About this study

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

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.

Conditions
Hunter Syndrome
Being tested
Control, Idursulfase IT (1 mg), Idursulfase IT (10 mg), Idursulfase IT (30 mg)
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
Medical subject headings
Mucopolysaccharidosis II, Mucopolysaccharidoses, Sudden Infant Death, Lysosomal Storage Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ControlOther

    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.

  • Idursulfase IT (1 mg)Drug

    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.

  • Idursulfase IT (10 mg)Drug

    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.

  • Idursulfase IT (30 mg)Drug

    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.

Study groups in NCT00920647
Study groupRoleWhat they receive
ControlOtherUntreated Patients
Receives: Other: Control
Idursulfase -IT (1 mg)Experimentalmonthly using an intrathecal drug delivery device (IDDD)
Receives: Drug: Idursulfase IT (1 mg)
Idursulfase-IT (10 mg)Experimentalmonthly using an intrathecal drug delivery device (IDDD)
Receives: Drug: Idursulfase IT (10 mg)
Idursulfase -IT (30 mg)Experimentalmonthly using an intrathecal drug delivery device (IDDD)
Receives: Drug: Idursulfase IT (30 mg)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Serious Adverse Event (SAE)

    Measured: 6 months

  2. Number of Treatment Emergent Adverse Event (AE)

    ITT patient population

    Measured: Baseline to week 23

  3. 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.

    Measured: 6 months

  4. Safety: Development of Anti-idursulfase Antibodies (CSF)

    Reflects development of anti-idursulfase antibodies post baseline.

    Measured: 6 months

  5. Safety: Development of Anti-idursulfase Antibodies (Serum)

    Measured: 6 months

  6. 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.

    Measured: 6 months

Secondary outcomes (5)

  1. Change From Baseline in CSF Glycosaminoglycans [GAGs] at Week 27

    Percent Change from Baseline to Week 27

    Measured: Baseline to Week 27

  2. 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)

    Measured: Week 27 (end of study)

  3. 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.

    Measured: Weeks 3

  4. Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase

    Measured: Weeks 23

  5. % Change From Baseline in Urinary GAG

    Measured: Baseline to Week 27

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jun 2009 (estimated)
  2. Study start18 Nov 2009
  3. Primary completion29 Oct 2012
  4. Study completion29 Oct 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00920647
Sponsor's protocol ID
HGT-HIT-045
Other IDs
2010-020048-36
Status last verified
Jun 2021
First submitted
12 Jun 2009
Last updated
28 Jun 2021
Data monitoring committee
Yes
Individual data sharing
Yes: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

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.

    PubMed 25834948

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Idursulfase IT (1 mg), Idursulfase IT (10 mg) and Idursulfase IT (30 mg) in people with Hunter Syndrome, run by Shire at 3 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United Kingdom, United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 May 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Serious Adverse Event (SAE) (time frame: 6 months). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00920647, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jun 2021.

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