The primary objectives of this study is:* To determine the safety and tolerability of rhHNS via ascending doses administered via a surgically implanted intrathecal drug device (IDDD) once monthly for 6 months, in patientswith MPS IIIA.The secondary…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* To determine the safety of intrathecal rhHNS administration, as measured by
adverse events
(by type and severity), changes in clinical laboratory testing (serum chemistry
including liver
function tests, hematology, and urinalysis), electrocardiograms, CSF chemistries
(including cell counts and inflammatory markers), and anti-rhHNS antibodies (in
CSF and
serum).
Secondary outcome
* To determine (by dose group) the effects of IT administration of rhHNS, as
measured by
(1) change from baseline values, and (2) comparison to values obtained in a
longitudinal,
12-month, natural history study of untreated patients with MPS IIIA in the Shire
HGT-SAN-053 Surrogate Endpoint Trial, on the following measurements/
assessments over
a 6-month period:
* Standardized neurocognitive and behavioral assessments as measured by the
Bayley
Scales of Infant Development, Third Edition (BSID-III), and the Kaufman
Assessment
Battery for Children, Second Edition (KABC-II).
* Sanfilippo-specific behavioral rating scales, as measured by the Four-Point
Scoring
System/Total Disability Score (FPSS/TDS) and the Sanfilippo Behavioral Rating
Scale
(SBRS).
* Gross and fine motor skills assessment and voluntary movement, as measured by
the
Movement Assessment Battery for Children, Second Edition (MABC-2).
* Functional adaptive behavior as measured by the Vineland Adaptive Behavioral
Scales,
Second Edition (VABS-II).
* Quality of life (QoL), as measured by the Child Health Questionnaire* Parent
Form 50
(CHQ-50) Questions and Child Health Questionnaire* Child Form 87 (CHQ-87),
Infant
Toddler Quality of Life Questionnaire* (ITQOL), and Children*s Sleep Habits
Rating
Scale.
* Concentration of rhHNS in CSF and serum.
* Concentration of inflammatory cytokines in serum and CSF.
* Concentration of heparan sulfate and heparan sulfate derivatives in urine and
CSF, and, if
possible, in serum.
* Concentration of exploratory biomarkers in CSF, serum, and urine (potential
surrogate
markers of efficacy).
* Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR),
aka
Brainstem Auditory Evoked Potentials.
Background summary
Sanfilippo syndrome, or MPS (Mucopolysaccharidosis) III, is a lysosomal storage
disease (LSD) caused by loss in activity of one of four enzymes necessary for
degradation of the glycosaminoglycan (GAG) heparan sulfate in lysosomes. Four
different subtypes (A, B, C, and D) have been identified and are each due to a
specific enzyme deficiency involved in the lysosomal catabolism of heparan
sulfate. MPS IIIA results from deficiency of the enzyme heparan-N-sulfatase
(sulfamidase). In the absence of this enzyme, intermediates of the heparan
sulfate degradation process dramatically accumulate in the lysosomes of neurons
and glial cells, with lesser accumulation outside the brain.
MPS III is the most prevalent of all mucopolysaccharidoses; MPS IIIA is the
most frequent subtype in the Netherlands. Subtypes A and B together account for
approximately 90% of all cases of MPS III worldwide. The birth prevalence of
MPS IIIA has been estimated as 1.28 per 100,000 in Australia, 1.16 per 100,000
in the Netherlands, and 0.88 in 100,000 in Germany.1-3 In summary, there is
widespread geographic prevalence of MPS IIIA, with an average global birth
incidence of approximately 1 in 100,000.
MPS IIIA symptoms arise between 2 to 6 years of age for the majority of
patients who are severely affected; however, diagnosis often lags behind the
earliest symptoms. Patients present a wide spectrum and severity of clinical
symptoms. The central nervous system (CNS) is the most severely affected organ
system in patients with MPS IIIA, evidenced by deficits in language
development, motor skills, and intellectual development. In addition, there are
abnormal behaviors including but not limited to aggression and excess motor
activity/hyperactivity that contributes to disturbances in sleep.4-6 In
contrast with other MPS types, the viscera are mildly affected, with
enlargement of liver and spleen with no evidence of dysfunction. There are also
reports of unexplained, recurrent and severe diarrhea. Overall, individuals
with MPS IIIA have a marked developmental delay and significantly reduced
lifespan of 15 years of age on average. A milder variant has recently been
identified with slower progression and survival to later age in approximately
10% of German patients with MPS IIIA.
A long range goal of Shire Human Genetic Therapies (Shire HGT) is to develop
recombinant human heparan-N-sulfatase (rhHNS) enzyme replacement therapy (ERT)
for patients with MPS IIIA. A particular challenge for treating lysosomal
storage disorders that damage the brain (such as MPS III) is how to target ERT
to the brain. In ongoing animal studies, ERT is being administered into the
cerebral spinal fluid (CSF) via an intrathecal (IT) route, because when
administered intravenously (IV) it does not cross the blood brain barrier (BBB)
after the immediate postnatal period of life. The first precedent for
intraspinal ERT has been shown to be both safe and effective for spinal cord
compression in patients with MPS I.
In the current study recombinant human heparan-N-sulfatase (rhHNS) will be
administered via an inthrathecal route, and safety and efficicy will be
investigated.
Study objective
The primary objectives of this study is:
* To determine the safety and tolerability of rhHNS via ascending doses
administered via a surgically implanted intrathecal drug device (IDDD) once
monthly for 6 months, in patients
with MPS IIIA.
The secondary objectives of this study are:
* To determine by dose group the effects of IT administration of rhHNS, as
measured as
(1) change from baseline values, and (2) comparison to values obtained in a
longitudinal,
12-month, natural history study of untreated patients with MPS IIIA in the Shire
HGT-SAN-053 Surrogate Endpoint Trial, on the following measurements/assessments
over a
6-month period:
* Standardized neurocognitive and behavioral assessments, Sanfilippo-specific
behavioral
rating scales, gross and fine motor assessments, functional adaptive rating
scales, quality
of life questionnaires, and Children*s Sleep Habits Rating Scale.
* Concentration of rhHNS in cerebrospinal fluid (CSF) and serum.
* Concentration of safety and potential surrogate efficacy biomarkers in CSF,
urine, and
serum.
* Concentration of heparan sulfate and heparan sulfate derivatives in urine and
CSF as
measured over approximately 6 months.
* Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR),
aka
Brainstem Auditory Evoked Potentials.
Study design
This is a multicenter, multiple-dose, dose escalation study designed to
evaluate the safety,
tolerability, and clinical activity of up to 3 dose levels (10, 45 and 90 mg)
monthly for 6 months of rhHNS administered via an IDDD in patients with
Sanfilippo syndrome Type A.
Patients will be assigned to 1 of 3 treatment groups:
* Group 1: rhHNS administered by IT injection 10 mg once per month for a total
of 6 months
* Group 2: rhHNS administered by IT injection 45 mg once per month for a total
of 6 months
* Group 3: rhHNS administered by IT injection 90 mg once per month for a total
of 6 months
This study will have 7 periods as follows:
* Screening: Within 60 days prior to the implantation of the IDDD.
* Surgical implantation of the IDDD: Week 1, Days 1 through 7. Includes
pre-surgical
assessments, surgical implantation of the IDDD on Day 2, and follow-up
assessments on
Days 3 through 7 after operative procedure.
* Baseline: Week 2, Days 1 and 2. Assessments for safety, biochemical, and
neurological
baseline measures (Day 1) will occur on the day before the first IT injection.
CSF sample
assessment will be obtained from patients on Day 2, immediately prior to the
first IT study
drug injection.
* Treatment period: Week 2 (first IT administration) through Week 22, (last
IT administration). Intrathecal administration of rhHNS will occur on Day 2
(±2) days of
each dosing week (Weeks 2, 6, 10, 14, 18, and 22).
* End of study procedures: Week 26, 30 (±7) daysafter the last rhHNS
administration for patients who complete the study, and 30 (±7) days
after the last rhHNS administration for patients who discontinue prior to the
end of the study.
* Safety follow-up: Week 30, 30 (±7) days after the end of study procedures.
Intervention
At the start of the study patients will receive a surgically implanted
intrathecal drug
delivery device (IDDD). After this patients will receive Monthly or EOW
inthrathecal enzyme therapy.
Study burden and risks
The risks of the study are associated with various procedures. The risk to
anesthesia are not common but can include irregular heartbeat, increase or
decrease in blood pressure, a fast increase in body temperature, difficulty
breathing, heart attack or stroke, a reaction to a medication used in
anesthesia, or death from complications of changes in heartbeat, blood
pressure, body temperature, or breathing.
A lumbar puncture can cause a mild to severe headache, which may last for
several days. Risks associated with lumbar puncture include pain at the
injection site, meningitis (infection of the nervous system), failed procedure,
bleeding and spinal fluid leakage. To decrease the risk of headaches associated
with lumbar punctures, the subject will be asked to stay flat in bed for about
2 hours after the procedure is completed.
The risk of blood sampling may be mild pain and discomfort at the site of
needle entry. There is a slight risk of fainting, bruising, swelling or
infection at the site of needle entry.
Benefit: The subject will receive very close attention by the study staff
during the time involved in this study. Research is designed to benefit society
by gaining new knowledge, so the information gained may benefit others
diagnosed with MPS IIIA.
300 Shire Way
MA 02421,Lexington
US
300 Shire Way
MA 02421,Lexington
US
Listed location countries
Age
Inclusion criteria
1. a.)Patients have a documented deficiency in sulfamidase enzyme activity of *10% of the lower limit of the normal range as measured in fibroblasts or leukocytes (based on measurements by a laboratory that is acceptable to Shire HGT).
AND EITHER b or C
b.)Patients have a normal enzyme activity level of at least 1 other sulfatase (to rule out multiple sulfatase deficiency) as measured in fibroblasts or leukocytes (based on measurements by a laboratory that is acceptable to Shire HGT).
c.) Patients have 2 documented mutations (based on assessments by a laboratory that is acceptable to Shire HGT).
2. The patient is *3 years of age and has a developmental age above 1 year (developmental age will be determined by the screening neurocognitive and developmental tests).
3. Patients must be medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery, without placing an undue burden on the patient/patient's family.
4. The patient*s parent(s) or legal guardian must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form
Exclusion criteria
1. The patient has 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 patient has MPS IIIA behavioral-related issues, as determined by the Investigator that would preclude performance of study neurocognitive and developmental testing procedures.
3. The patient is pregnant, breast feeding, or is a female patient of childbearing potential who will not or cannot comply with the use of an acceptable method of birth control
4. The patient is blind and/or deaf
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions.
6. The patient or the patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
7. The Investigator may choose to exclude patients who have had complications resulting from prior lumbar punctures.
8. The patient has a CNS shunt.
9. The patient has skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
10. The patient has a history of poorly controlled seizure disorder.
11. The patient is currently receiving psychotropic or other medications, which in the Investigator*s opinion, would be likely to substantially confound test results and the dose and regimen of which cannot be kept constant throughout the study.
12. The patient cannot sustain absence from aspirin, non-steroidal medications, or medications that affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device implantation if applicable), or has ingested such medications within 1 week before any procedures in which any change in clotting activity would be deleterious.
13. The patient has received treatment with any investigational drug or a device intended as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently enrolled in another study that involves an investigational drug or device (screening through safety follow-up contact).
14. The patient has received a hematopoietic stem cell or bone marrow transplant.
15. The patient*s parent(s), or patient*s legal guardian(s) is/are unable to provide consent or the patient cannot provide assent,
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 | EUCTR2009-015984-15-NL |
| CCMO | NL31033.018.10 |