The primary objective of this study is to assess the potential clinical efficacy of HGT-1410administered via a surgically implanted IDDD in patients with MPS IIIA. Efficacy will bemeasured as a meaningful amelioration in the progression of cognitive…
ID
Source
Brief title
Condition
- Metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Achievement of response, defined as a maximum decline in cognitive DQ of 10
points
over 48 weeks, as assessed by the Bayley Scales of Infant Development, 3rd
Edition.
Secondary outcome
- Safety endpoints including the assessment of adverse events (AEs), IDDD
related
issues, laboratory values, anti-rhHNS antibody development, vital signs,
physical
examination findings, and ECG results
-The change from baseline to Week 48 in adaptive behavioral function, assessed
by
VABS II, using raw scores and age equivalent score
- The change from baseline to Week 48 in the DQ assessed by neurocognitive
testing, using the BSID-III age equivalent scores
- The change from Baseline to Week 48 in total cortical grey matter volume, as
assessed by MRI
- The change from Baseline to Week 48 in concentrations of GAG in the CSF and
urine
- The concentration of HGT-1410 in CSF and serum
Background summary
MPS IIIA is a rare, inherited genetic disorder in which an enzyme called
heparan N-sulfatase (HNS) or sulfamidase is missing or not working properly.
This enzyme is important in the breakdown of mucopolysaccharides (MPSs) or
glycosaminoglycan (s) (or GAGs), which are large complex sugars used in the
building of tissues of the body. When sulfamidase is missing, or not working
properly, it causes GAGs to build up in the body, in the small parts of the
cells, called lysosomes. As time goes on, cells in the body become clogged
with the sugar and are injured. As a result, patients with MPS IIIA develop
problems affecting the body, especially the central nervous system (CNS: the
brain and spinal cord). These patients typically do not develop normal
abilities regarding language, learning, and many of the normal tasks that are
part of growing up or the patients may develop these abilities and then lose
them as time goes on and the GAGs build up within their body. The study
Sponsor, Shire HGT, is developing the study drug, recombinant human heparan
N-sulfatase (rhHNS; HGT-1410) as an enzyme replacement therapy (ERT) for
patients with MPS IIIA.
Study objective
The primary objective of this study is to assess the potential clinical
efficacy of HGT-1410
administered via a surgically implanted IDDD in patients with MPS IIIA.
Efficacy will be
measured as a meaningful amelioration in the progression of cognitive decline,
and will be
measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition
(BSID-III).
Secondary objectives:
To determine:
* The safety and tolerability of HGT-1410 IT
* The effect of HGT-1410 administration on BSID-III Age-equivalent and
development
quotient (DQ) scores
* The effect of HGT-1410 IT on adaptive behavioral function, assessed by
Vineland Adaptive
Behavior Scales, Second Edition (VABS II)
* The effect of HGT-1410 IT treatment on the total cortical grey matter volume,
as assessed by
volumetric MRI of the brain
* The effect of HGT-1410 IT treatment on the concentration of GAGs in CSF and
urine
* The pharmacokinetics of HGT-1410 in CSF and serum.
Study design
This is an open-label, randomized, parallel group, controlled, multicenter
study designed
to evaluate the efficacy and safety of 45 mg HGT-1410 administered IT Q2W and
45 mg
of HGT-1410 administered IT Q4W via an IDDD versus no treatment in patients at a
relatively early stage of MPS IIIA disease. Cognitive assessments, which
support the primary objective of the trial, will be performed by assessors who
are blinded to the treatment assignment of the patient.
Intervention
HGT-1410 at a dose of 45 mg administered every 2 weeks (Q2W) or 45 mg
administered
every 4 weeks (Q4W). HGT-1410 will be administered intrathecally (IT) by an
indwelling
intrathecal drug delivery device (IDDD).
The SOPH-A-PORT® Mini S is a system intended for implantation by physicians. The
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer
HGT-1410 indicated for IT delivery intermittently over a long period.
The comparator group will receive no treatment with HGT-1410. A placebo will
not be
used, since the IDDD will not be implanted in patients who are randomized to
the control
group.
HGT-1410 Q2W (ie, every 14 days), or Q4W (ie, every 28 days) for 48 weeks via a
surgically implanted intrathecal drug delivery device (IDDD), or lumbar
puncture (LP)
Study burden and risks
Please refer to the overview of procedures in the protocol (appendix 1) for a
complete overview.
The following procedures will be performed in the context of the research and
are different/additional in comparison with the standard treatment:
All treatment groups:
-complete questionnaires (3 times)
-lumbar punction (3 times in non-treatment group), in the treatment groups if
cerebrospinal fluid cannot be collected by IDDD device;
-MRI (3 times)
Only treatment groups:
-intake IP
-implementation of IDDD
-x-rays (2 times). Possibly 12 additional x-ray studies to verify proper
placement of the device if there are problems accessing the device.
Pain and headache during or after the injection of study drug are possible. The
injection procedure may be performed incorrectly, including injecting the wrong
medicine through the port, injecting study drug outside the port into the
surrounding tissue, or using the wrong type of needle or improper technique
while injecting medicine into the port.
Injection of HGT-1410, as with any protein, carries with it the risk of an
infusion-related reaction.
Tingling or painful sensation to the lower legs.
Shire Way 300
Lexington MA, 02421
US
Shire Way 300
Lexington MA, 02421
US
Listed location countries
Age
Inclusion criteria
1. Documented MPS IIIA diagnosis:
a) All patients must show a documented deficiency in sulfamidase
enzyme activity of *10% of the lower limit of the normal range as
measured in fibroblasts or leukocytes
AND
b) patients must show documented mutations in each SGSH allele OR there must be
documentation of mutations in each SGSH allele in a sibling affected by
MPSIIIA, provided parental consent is obtained to use this information.
2. Age *12 months and * 48 months
3. The patient has a Developmental Quotient score *60%, assessed by
cognitive evaluation at screening assessment using the Bayley Scales of
Infant and Toddler Development *3rd Edition (BSID-III)
4. The patient is medically stable, in the opinion of the Investigator, and
able to accommodate the protocol requirements, including travel,
assessments, and IDDD surgery, without placing an undue burden on the
patient/patient's family
5. The patient, and patient's parent(s) or legal guardian must have
voluntarily signed an Independent Ethics Committee-approved informed
consent form after all relevant aspects of the study have been explained
and discussed with the patient's parent(s), or legal guardian. Consent of
the patient's parent(s) or legally authorized guardian(s) must be
obtained prior to the start of any study procedures.
Exclusion criteria
1. The presence of significant non-MPS IIIA related central nervous
system (CNS) impairment or behavioral disturbances that would
confound the scientific integrity or interpretation of study assessments,
as determined by the Investigator.
2. The presence of the S298P mutation in either or both SGSH alleles,
associated with attenuated disease OR there must be documentation of
mutations in each SGSH allele in a sibling affected by MPSIIIA, provided
parental consent is obtained to use this information.
3. The presence of relatively attenuated MPS IIIA disease in an older
sibling, defined as preservation of any comprehensible speech beyond
the age of 10 years
4. Visual or hearing impairment, in the clinical judgement of the
investigator, sufficient to preclude cooperation with neurodevelopmental
testing.
5. In the opinion of the Investigator, the patient is assessed as having an
unacceptably high risk for anesthesia due to airway compromise, drug
hypersensitivity, or other conditions (such as neuroleptic malignant
syndrome, malignant hyperthermia, or other anesthesia-related
concerns).
6. The patient has a history of poorly controlled seizure disorder.
7. The patient is currently receiving psychotropic or other medications,
which in the Investigator's opinion would be likely to substantially
confound test results.
8. The patient has a history of bleeding disorder or is unable to abstain
from medications that, in the opinion of the investigator, place them at
risk of bleeding following surgery or lumbar puncture..
9. The patient participated in a clinical trial of another investigational
medicinal product, within the 30 days prior to the study (or within 5
elimination half lives of the investigational product), or is currently
enrolled in another study that involves an investigational drug or device.
NOTE: Nutritional supplements, including genistein are permitted if they
are taken or administered outside the context of a formal investigation.
10. The patient has received a hematopoietic stem cell or bone marrow
transplant, or gene therapy.
11. The patient has a condition that is contraindicated as described in
the SOPH-A-PORT Mini S IDDD Instructions for Use, including:
a) The patient has had 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-APORT
Mini S Access Port, as judged by the Investigator
c) The patient has a known or suspected local or general infection
d) The patient has one or more spinal abnormalities that could
complicate safe implantation or fixation
e) The patient has a functioning CSF shunt device
f) The patient has shown an intolerance to an implanted device
12. The patient's parent(s) or patient's legal guardian(s) is/are unable
to understand the nature, scope, and possible consequences of the
study, or do/does not agree to comply with the protocol defined
schedule of assessments.
13. The patient is unable to comply with the protocol (eg, has a clinically
relevant medical condition making implementation of the protocol
difficult, unstable social situation, or otherwise unlikely to complete the
study) or is, in the opinion of the Investigator, otherwise unsuited for
the study.
14. The patient has any item (braces, tattoos, etc.) which would exclude
the patient from being able to undergo MRI according to local
Institutional Policy, or the patient has any other situation that would
exclude the patient from undergoing any other procedure required in
this study.
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR201300345024-NL |
| ClinicalTrials.gov | NCT02060526 |
| CCMO | NL46471.018.13 |