The objective of this study is to identify and develop laboratory measurements and other tests that may help develop treatments for Hunter Syndrome and, potentially, related diseases. The information learned from this study may also help doctors,…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* To characterize the progression of adaptive behavior as measured by the
Vineland Adaptive Behavior Scales (VABS)
* To characterize the progression of neurocognition as measured by the Bayley
Scales of Infant and Toddler Development, Third Edition (BSID-III); Kaufman
Assessment Battery for Children*, Second Edition (KABC-II); or Wechsler
Intelligence Scale for Children*, Fifth Edition (WISC-V)
* To assess levels of potential disease-related or treatment-responsive
biomarkers in blood, urine, and/or cerebrospinal fluid (CSF) samples from MPS
II participants
Secondary outcome
The exploratory objectives of the study are as follows:
*To explore correlations between disease-related biomarkers and clinical
measures of disease severity (e.g., function, cognition, and behavior)
*To characterize glycosaminoglycan (GAG) levels in serum and urine of MPS II
participants
*To characterize GAG levels in the CSF of MPS II participants
Background summary
Early medical care is likely required to prevent the disabling damages to the
brain seen in Hunters syndrome. Currently known biomarkers do not reliably
predict disease severity, disease progression, and treatment response in
Hunters syndrome, especially in younger children, and evaluation of new
potential biomarkers is needed.
Study objective
The objective of this study is to identify and develop laboratory measurements
and other tests that may help develop treatments for Hunter Syndrome and,
potentially, related diseases. The information learned from this study may also
help doctors, healthcare professionals and researchers understand more about
your child*s condition and other people with Hunter Syndrome.
Some of the laboratory tests in this investigational study will be done to find
out how Hunter Syndrome works in the body and to determine how your child*s
body is managing Hunter Syndrome. These tests measure substances called
biomarkers. The research being done in this study may determine how future
therapies (medications and procedures) can work to help manage Hunter Syndrome.
In this study, the biomarkers being measured can be found in blood, urine and
cerebrospinal fluid (CSF), samples of which are planned to be collected during
this trial .
Study design
This is a nonrandomized, prospective, observational study of patients diagnosed
with MPS II, also known as Hunter syndrome. There are no experimental therapies
in this study. The primary focus is to evaluate biomarkers and assess the
clinical outcomes of disease in patients with MPS II, including the
neuronopathic form of mucopolysaccharidosis type II (nMPS II),and the
non-neuronopathic form of mucopolysaccharidosis type II (nnMPS II), that
Biomarkers and their correlation to clinical progressiont may serve as markers
of disease severity or treatment response, and thereby advance clinical trials
of new MPS II therapeutics.
Documented diagnosis of MPS II is required for study entry in all parts of the
study. This diagnosis will include genetic analysis (mutation analysis of the
iduronate-2 sulfatase [IDS] gene) and biochemical assessment (e.g., IDS enzyme
activity in plasma, white blood cells, or fibroblasts).
Before enrollment for Parts 3 and 4 begins,Part 1 of the study will have
enrolled approximately 11 participant from 2 through 10 years of age who have
MPS II and Part 2 of the study will have enrolled approximately 2 participants
from 2 through 30 years of age who have MPS II.
Part 3 will enroll approximately 12 participants who are < 8 years of age at
screening and have nMPS II, and Part 4 will enroll approximately 12
participants aged 6 to < 17 years at screening who have nnMPS II.
In Part 1, biomarker sample collections will occur primarily in the first month
of the study and at Month 6, and patients will be followed for up to 18 months,
or until they enroll into Part 3 or 4 of the study or one of the planned
treatment trials. In Parts 3 and 4, clinical outcome assessments and blood and
urine biomarker sample collections will be performed, and participants will be
followed for up to 24 months.
In Part 1, approximately 11participants aged 2 through 10 years who have MPS II
will be enrolled, as follows:
*Approximately 5 (one-half) or more of enrolled patients will be aged 2
through 5 years.
*Approximately 3 (one-third) or more of all enrolled patients will have
aneuronopathic phenotype.
In Part 2, Approximately 2 patients from 2 through 30 years of age who have MPS
II will be enrolled; Part 2 will entail a single collection of urine, and blood.
Clinical assessments are optional in Part 2 for patients aged 18 years or
younger;
no clinical assessments are planned for patients older than 18 years.
Approximately 4 or more of enrolled patients in Part 2 will have a neuronopathic
phenotype.
Part 1 and Part 2 will be conducted concurrently. until approval of Version 6
of the DNLI-E-0001 Protocol has been obtained from each site. After the
amendment has been approved, no further participants will be enrolled in Part 1
or 2 of the study. Ongoing participants active in Part 1 at the time of
approval have the option of being screened for Part 3 or 4 and switching to
Part 3 or 4, if eligible. Otherwise, participants will complete the remaining
Part 1 assessments per the schedule of assessments.
In Part 3, approximately 12 participants aged < 8 years at screening who have
nMPS II will be enrolled as follows:
* At least 6 (or one-half) of the enrolled participants will be < 3 years of
age at screening, including newborns.
In Part 4, approximately 12 participants aged 6 to < 17 years at screening who
have nnMPS II will be enrolled as follows:
* At least 8 (or two-thirds) of the enrolled participants will be < 13 years of
age at screening.
Study burden and risks
Patients age 19 to 30 years old; study participation will last for
approximately 2 months. This time will include the screening period, visit Day
1 and safety follow-up. A visit will take about 3 to 4 hours.
Patients age 16 to 18 and agree to undergo optional assessments will take part
in the study for up to approximately 5 months. This time will include the
screening period, visit Day 1, additional, optional tests provided with
agreement from you and at the discretion of the doctor, and the safety
follow-up. The visits with optional assessments will take about 4 to 5 hours.
While being in this study, blood, urine, saliva (if required) and
cerebrospinal fluid samples are taken. If required, approximately 1-2 mL of
saliva will be collected. During the screening visit approximately 5 mL and
during visit Day 1 approximately 10 mL of blood may be collected. If the entire
study is completed, the total amount of blood collected will be approximately
15 mL. At the study visits where cerebrospinal fluid is collected, up to
approximately 10 mL of cerebrospinal fluid may be collected during each lumbar
puncture. If a CSF sample is provided and complications develop, it may be
necessary to collect additional blood for safety purposes.
Some of the questions on the rating scales and questionnaires may seem
personal. Patients may refuse to answer any of the questions.
Patients in the current study will not receive any additional medical therapy
for MPS II, and, as such, are not expected to receive direct therapeutic
benefit. However, they may benefit from participation in this study via the
included assessments of health status and information that may be used to
request educational, medical, or other services. For example, some patients
will undergo neurocognitive evaluations, and the test results will be provided
to the parent(s)/legally authorized representative (LAR), which may be used to
determine and request additional educational services. Hearing loss is a common
feature of MPS II; audiology assessments performed in this study will
characterize patients* hearing performance, and the results may be used to plan
treatments or interventions.
The risks of participation in the current study are primarily those associated
with the study procedures, including blood draws. All procedures will be
performed by medical staff with expertise in the care of MPS II patients.
Oyster Point Blvd. 161
South San Francisco CA 94080
US
Oyster Point Blvd. 161
South San Francisco CA 94080
US
Listed location countries
Age
Inclusion criteria
Part 1 and 2
Participants in Parts 1 and 2 must have a confirmed diagnosis of MPS II based
on the following:
1) A documented mutation in the IDS gene, AND
2) Reduced IDS activity in plasma, WBCs, and/or skin fibroblasts consistent
with MPS II (e.g., *10% of the lower limit of the normal range, based on the
testing laboratory*s range)
For nMPS II subgroups in Parts 1 and 2participants will have a neuronopathic
phenotype at the time of enrollment based on the following criteria:
* In addition to a diagnosis of MPS II, have a development quotient (DQ) <85
and/or a decline of at least 7.5 points in DQ, assessed at least 6 months
apart, or have the same genetic mutation as a blood relative with confirmed
nMPS II
Part 1
Participants in Part 1 must also meet the following criteria for study entry:
* Informed consent signed by the parent(s) or LAR and participant assent if
required based on local regulations, IRB/IEC requirements, and patient age
* Aged 2 through 10 years at time of consent
* Participant and parent(s) or LAR are willing and able to comply with study
visits and study procedures
* Have the ability to comply with protocol requirements according to the
investigator*s judgment
Part 2
Participants in Part 2 must also meet the following criteria for study entry:
* Consent:
o For minors: informed consent signed by the parent(s) or LAR and participant
assent if required based on local regulations and patient age
o For nonminors: informed consent signed by the participant
* Aged 2 through 30 years at time of consent
* Participant and parent(s) or LAR are willing and able to comply with study
visits and study procedures
* Have the ability to comply with protocol requirements according to the
investigator*s judgment
* Scheduled to undergo CSF sampling for non-study-related medical reasons and
participant or parent(s)/LAR consent to donate CSF for research purposes during
that procedure.
Part 3
Participants in Part 3 must meet the following criteria for study entry:
* Have informed consent signed by the parent(s) or LAR and participant assent
if required based on local regulations, IRB/IEC requirements, and participant
age
* Be < 8 years of age at time of consent
* At least 6 (or one-half) of the participants enrolled must be < 3 years of
age at screening
* Have a confirmed diagnosis of MPS II based on all of the following criteria:
* 1. Documented reduced IDS activity in plasma, WBCs, and/or skin fibroblasts
consistent with MPS II (10% or less of the lower limit of the normal range,
based on the testing laboratory*s range)
* 2. Elevated urine GAG levels consistent with MPS II diagnosis:
* a. At screening in standard-of-care ERT treatment-naïve participants
* b. Pretreatment in participants receiving standard-of-care ERT, if available
by historical report
* 3. A documented likely pathogenic variant in the IDS gene, as determined by
an independent external review panel
* *Have nMPS II based on at least one of the criteria (1, 2, or 3) below:
1. Have a large deletion(s) or rearrangement(s) in the IDS gene or
other definitive mutation indicative of nMPS II, as determined by an
independent external review panel
2. Have a DQ > 55 and < 85 at the baseline neurocognitive assessment
and/or a documented decline of at least 7.5 points in DQ in the previous 6 to
18 months
3. Have the same IDS gene variant as a blood relative with confirmed
nMPS II
* Participant and parent(s) or LAR are willing and able to comply with study
visits and study procedures.
* Have the ability to comply with protocol requirements according to the
investigator*s judgment
Part 4
Participants in Part 4 must meet the following criteria for study entry:
* Have informed consent signed by the parent(s) or LAR and participant assent
if required based on local regulations, IRB/IEC requirements, and participant
age
* Be 6 to < 17 years of age at time of consent
* At least 8 (or two-thirds) of the participants enrolled must be < 13 years of
age at screening
* Have a confirmed diagnosis of MPS II based on all of the following:
* 1. Documented reduced IDS activity in plasma, WBCs, and/or skin fibroblasts
consistent with MPS II (10% or less of the lower limit of the normal range,
based on the testing laboratory*s range)
* 2. Elevated urine GAG levels consistent with MPS II diagnosis:
At screening in standard-of-care ERT treatment-naïve participants
b. Pretreatment in participants receiving standard-of-care ERT, if
available by historical report
3. A documented likely pathogenic variant in the IDS gene, as
determined by an independent external review panel
* Have nnMPS II based on both of the following:
1. Do not have a large deletion(s) or rearrangement(s) in the IDS gene
or other definitive mutation indicative of nMPS II, as determined by an
independent external review panel
2. The participant has a General Ability Index (GAI) score * 70 at the
baseline assessment based on the WISC-V, performed without clinically
significant hearing loss or with hearing aids presentHave a full-scale
intelligence quotient (IQ) above 70 at the baseline assessment based on the
WISC-V performed
* Participant and parent(s) or LAR are willing and able to comply with study
visits and study procedures.
* Have the ability to comply with protocol requirements according to the
investigator*s judgment
Exclusion criteria
Patients who meet any of the following criteria will be excluded from study
entry (Part 1 and Part 2):
* Have an unstable medical condition that would make participation in the study
unsafe or would interfere with necessary medical care, in the opinion of the
investigator
* Have received any CNS-targeted MPS II investigational therapy (e.g.,
intrathecal IDS, transferrin or insulin receptor*mediated IDS delivery to CNS,
or stem cell transplantation) within the previous 6 months. Patients may
rescreen for this study after the 6-month washout completes.
* Have received an MPS II gene therapy at any time
* Have a mutation of other genes, including loci adjacent to the IDS gene
(e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e.,
AFF2 or FMR2]), that are known to be associated with developmental delay,
seizures, or other significant CNS disorders
* Have documented loss of activity of sulfatases other than IDS, indicating
multiple sulfatase deficiency
Patients in Part 2 who meet any of the following criteria will be excluded from
study entry:
* Have a history of complications from previous LPs or are anticipated to pose
significant technical challenges or unacceptable safety risk in receiving an
LP, in the judgment of the investigator
* Have any bleeding disorders, or any other medical condition or circumstance
in which an LP (for collection of CSF) is contraindicated according to local
institutional policy
Participants who meet any of the following criteria will be excluded from Parts
3 and 4 study entry:
* Have an unstable medical condition that would make participation in the study
unsafe or would interfere with necessary medical care, in the opinion of the
investigator
* Have received any CNS-targeted MPS II investigational therapy (e.g.,
intrathecal IDS, transferrin or insulin receptor*mediated IDS delivery to CNS,
or stem cell transplantation) within the previous 6 months
* Have received an MPS II gene therapy or hematopoietic stem cell transplant at
any time unless prior Sponsor approval has been received
* Have a mutation of other genes, including loci adjacent to the IDS gene
(e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e.,
AFF2 or FMR2]), that is known to be associated with developmental delay,
seizures, or other significant CNS disorders
* Have documented loss of activity of sulfatases other than IDS, indicating
multiple sulfatase deficiency
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04007536 |
| CCMO | NL72007.078.19 |