Peadiatric study of Idursulfase-IT with Elaprase® in patients with Hunter Syndrome and early cognitive impairment

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2013-002885-38-GB
• Date of registration: 11/09/2013
• Prospective Registration: Yes
• Primary sponsor: Shire HGT Inc
• Public title: Peadiatric study of Idursulfase-IT with Elaprase® in patients with Hunter Syndrome and early cognitive impairment
• Scientific title: A Controlled,Randomized,Two-arm,Open-label,Assessor-blinded,Multicenter Study of Intrathecal Idursulfase-IT Administered in Conjunction with Elaprase® in Pediatric Patients with Hunter Syndrome and Early Cognitive Impairment.
• Date of first enrolment: 22/10/2013
• Target sample size: 54
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002885-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: yes; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Patients are assigned randomly to participate without receiving IT treatment; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Canada, Colombia, France, Germany, Mexico, Spain, United Kingdom, United States

Contacts

• Name: Helen Fitch
• Affiliation: Shire HGT

• Name: Helen Fitch
• Affiliation: Shire HGT

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion Criteria for the Pivotal Study:
- The patient is male and is =3 and <18 years of age at the time of informed consent.
- The patient must have a documented diagnosis of MPS II. Of the three criteria below, the combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS II:
a. The patient has 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 the reference laboratory’s normal range).
AND
b.The patient has a documented mutation in the iduronate-2-sulfatase gene that leaves the FMR1 and FMR2 genes intact.
OR
c.The patient has a normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on the normal range of measuring laboratory).
- The patient has evidence at Screening of Hunter syndrome-related cognitive impairment, defined as follows:
A patient who is =3 and <13 years of age must have one of the following criteria (3a OR 3b):
a. A GCA score =55 and =85
OR
b. If the patient has a GCA score at Screening >85, there must be evidence of a decrease in GCA score of =10 points over 12 months from a previously documented test result in observational study HGT-HIT-090.
A patient who is =13 and <18 years of age must have both of the following criteria (3c AND 3d):
a. A GCA score of =55 and =85.
AND
b. There must be evidence of a decrease in GCA score of =10 points over 12 months from a previously documented test result in observational study HGT-HIT-090.
- The patient has received and tolerated a minimum of 4 months of therapy with Elaprase during the period immediately prior to Screening.
- The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the Investigator’s judgment to complete the required protocol testing and must be compliant with wearing the hearing aid(s), if needed, on scheduled testing days.

Inclusion criteria for the sub-study:
- The patient is male and is <3 years of age at the time of informed consent.
- The patient must have a documented diagnosis of MPS II. Of the three criteria below, the combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS II:
a. The patient has 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 the reference laboratory’s normal range).
AND
b. The patient has a documented mutation in the iduronate-2-sulfatase gene that leaves the FMR1 and FMR2 genes intact.
OR
c. The patient has a normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on the normal range of measuring laboratory).
- The patient has evidence at Screening of Hunter syndrome-related cognitive impairment as assessed using the BSID-III and defined as a composite score on the cognitive scale =55 and =85.
- The patient has received and
Exclusion criteria:
- The patient has clinically significant non-Hunter syndrome-related CNS involvement (such as Fragile-X syndrome) which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
- The patient has a large chromosomal deletion or complex rearrangement that includes a deletion of the FMR1 and/or FMR2 genes.
- The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
- The patient has contra-indications for performance of lumbar puncture such as musculoskeletal/spinal abnormalities or risk of abnormal bleeding.
- 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 has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O.
- The patient has experienced infusion-related anaphylactoid event(s) 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 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 has a history of poorly controlled seizure disorder.
- The patient is unable to comply with the protocol (eg, 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 is enrolled in another clinical study that involves clinical investigation or use of any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to study enrollment or at any time during the study.
- 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 condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU), including:
a. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device
b. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator
c. The patient’s drug therapy requires substances known to be incompatible with the materials of construction
d. The patient has a known or suspected local or general infection
e. The patient is at risk of abnormal bleeding due to a medical condition or therapy
f. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation
g. The patient has a functioning CSF shunt device
h. The patient has shown an intolerance to an implanted device

Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

Long-term treatment of Hunter syndrome and cognitive impairment
MedDRA version: 20.0 Level: PT Classification code 10056889 Term: Mucopolysaccharidosis II System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: Idursulfase-IT
Product Code: HGT-2310
Pharmaceutical Form: Solution for injection
INN or Proposed INN: IDURSULFASE
CAS Number: 50936-59-9
Current Sponsor code: HGT-2310
Other descriptive name: idursulfase-IT
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Secondary Objective: Key secondary
To determine the effect of the treatment regimen in pediatric patients with Hunter syndrome and early cognitive impairment on the Adaptive Behavior Composite (ABC) score as measured by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II), in conjunction with Elaprase therapy

Secondary
To determine the effect of the treatment regimen in pediatric patients with Hunter syndrome and early cognitive impairment, in conjunction with Elaprase therapy, on:
- Cognitive function as measured by the cluster areas and subtests of the DAS-II
- Adaptive behavior as measured by the domains of the VABS-II

For safety, device, PK/PD and health status see protocol section 2.4 - 2.6

Main Objective: To determine the effect of the treatment regimen in pediatric patients with Hunter syndrome and early cognitive impairment on the General Conceptual Ability (GCA) score as measured by the Differential Ability Scale, Second Edition (DAS-II), in conjunction with Elaprase therapy

Primary end point(s): Change from baseline in the GCA score after 12 months of treatment, at Visit Week 52, as obtained by DAS-II testing

Timepoint(s) of evaluation of this end point: Screening, Weeks 16, 28, 40 and 52

Secondary Outcome(s)

Secondary end point(s): - Change from baseline in the adaptive behavior composite (ABC) score after 12 months of treatment at Visit Week 52, as obtained by VABS-II testing
- Change from baseline to Visit Weeks 16, 28, and 40 in the GCA score as obtained by DAS-II testing
- Change from baseline to Visit Weeks 16, 28, and 40 in the ABC score as obtained by VABS-II testing
- Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores in cluster areas of the DAS-II: Verbal, Nonverbal, Spatial, and Special Nonverbal Composite (SNC)
- Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores of the VABSII domains: Communication, Daily Living Skills, Socialization, and Motor Skills
- Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, developmental quotients, and T-scores for the subtests of the DAS-II: Verbal Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, Matrices, and Copying for the DAS-II/Early Years and Recall of Designs, Word Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential and Quantitative Reasoning for the DAS-II/School Years
- Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, developmental quotients, and V-scale scores of the VABS-II subdomains: Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills), Motor Skills (Gross, Fine)
- Change from baseline to Visit Weeks 16, 28, 40, and 52 in the V-scale scores and observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its subscales (Internalizing, Externalizing)

Pharmacokinetic and Pharmacodynamic Endpoints:
- Serum concentration of idursulfase and serum PK parameters after IT administration
- CSF concentration of idursulfase prior to each monthly IT administration
- Change from baseline in the concentration of GAG in CSF

Safety Assessments:
Safety will be assessed during the study by collection of adverse events (by type, severity, and relationship to treatment [idursulfase-IT, the IDDD, device surgical procedure, or IT administration process] and IV Elaprase infusion), changes in clinical laboratory testing (serum chemistry, hematology, urinalysis), physical and neurological examination, vital signs, 12-lead ECG recordings, CSF laboratory parameters (chemistries, cell counts), anti-idursulfase antibodies in CSF and serum, and determination of antibodies having enzyme neutralizing activity.

SOPH-A-PORT Mini S Device Assessments:
SOPH-A-PORT Mini S assessments will include measures of device implantation, device function, device longevity, record of revisions, removals, and replacements of the implanted IDDD, and adverse events associated with the device. This data will be collected on the patient’s case report form (CRF) from the time of implantation and continue throughout the study as long as the SOPH-A-PORT Mini S remains implanted.

- Health Status Assessment
Health status dimensions as obtained by the EQ-5D questionnaire.

Timepoint(s) of evaluation of this end point: Neurodevelopment assessments: Screening, Weeks 16, 28, 40 and 52

For all other endpoints please refer to Appendix 1, 2 and 3 of the protocol.

Secondary ID(s)

HGT-HIT-094

Source(s) of Monetary Support

Shire HGT

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 13/04/2018
• Date Completed: 28/09/2017
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002885-38/results