The primary objectives of this study are: • To determine the longterm safety and tolerability of rhHNS administered via an intrathecal (IT) route once monthly for 8 years in patients with MPS IIIA, who have received and tolerated 6 months of…
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Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• To determine the longterm 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), CSF chemistries (including cell counts and inflammatory
markers), and anti-rhHNS antibodies (in CSF and serum).
Secondary outcome
• To determine (by dose group) the longterm effects of IT administration of
rhHNS
• 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 inflammatory cytokines in serum and CSF untill amendment 6.
Concentration of rhHNS in CSF and serum
• 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 untill month 54, 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 Nederlands. 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.7 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. 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. The current study is an extension study of the HGT-SAN-055
study, by which recombinant human heparan-N-sulfatase (rhHNS) will be
administered via an inthrathecal route, and longterm safety and efficacy will
be investigated.
Study objective
The primary objectives of this study are:
• To determine the longterm safety and tolerability of rhHNS administered via
an intrathecal (IT) route once monthly for 8 years in patients with MPS IIIA,
who have received and tolerated 6 months of enzymetherapie in the HGT-SAN-055
study
• To determine the safety, tolerability, and patency of a surgically implanted
intrathecal drug delivery device (IDDD) in patients with MPS IIIA.
The secondary objectives of this study are:
• To determine by dose group the long term effects of IT administration of
rhHNS, • 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 8 years.
• Brain magnetic resonance imaging (MRI) and until month 54 also auditory
brainstem response (ABR), also called Brainstem Auditory Evoked Potentials.
Study design
This is a multicenter, open-label, multiple-dose, extension study designed to
evaluate the longtern safety, tolerability, and clinical activity of two dose
levels (45 and 90 mg monthly for 6 years) of rhHNS administered via an IDDD in
patients with Sanfilippo syndrome Type A. The patients previously in the 10 mg
per month treatment group, will be moved (after their written consent) to the
45 mg per month treatment group. Thus, from implementation of protocol
amendment 4, there will only be 2 treatment groups (arms):
• Group 1: rhHNS administered by IT injection 45 mg once per month
• Group 2: rhHNS administered by IT injection 90 mg once per month. This
extension study will last 8 years.
Patient will be screened by completion of the HGT-SAN-055 study. After this
patient will receive monthly intrathecal ERT. When patient receives ERT he will
have to stay in the hospital for at least 4 hours after the adminstration of
rhHNS. With every visit urine, blood en liquor will be collected. After month
54, collection of blood and urine will be reduced to every 3 months. On yearly
basis neurocognitive assessments, questionnaires, vision and hearing
assessments, MRI and ABR will be performed. ABR won't be conducted after month
54. MRI and ABR will be under genereal anaesthesia, if deemed necessary by the
investigator.
Intervention
In the HGT-SAN 055 study patients have received an surgically implanted
intrathecal drug delivery device (IDDD) where they received 6 months of enzyme
therapy. Patients will continue monthly inthrathecal enzyme therapy for 8
years. After implementation of protocol amendment 4, the Smith Medical IDDDs
shall be switched to another manufacturer's IDDD (Sophysa). This will only
occur if the IDDD currently in place, will show signs of dysfunctioning.
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 active
drug during the period of the study which may halt the cognitive decline.
Research is designed to benefit society by gaining new knowledge, so the
information gained may benefit others diagnosed with MPS IIIA.
Shire Way 300
Lexington MA 02421
US
Shire Way 300
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
Patients must meet all of the following criteria to be considered eligible for enrollment:
1. The patients must have completed Study HGT-SAN-055 and, in the opinion of the investigator, has no safety or medical issues that contraindicate participation.
2. The patient, patient*s parent(s), or legally authorized representative has voluntarily signed an Institutional Review Board / Independent Ethics Committee-approved informed consent (and assent, if applicable) form after all relevant aspects of the study have been explained and discussed with the patient, patient*s parent(s), or legally authorized representative's consent and patient*s assent, as appropriate, must be obtained prior to any study specific procedures.
3. The patient has received at least 5 of the 6 planned infusions of rhHNS in the study HGT-SAN-055 study.
4. Patients must be medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery (if necessary for replacement purposes), without placing an undue burden on the patient/patient's family.
Exclusion criteria
Subjects will be excluded from the study if there is evidence of any of the following criteria at screening or at anytime during the study:
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that contraindicates further treatment with rhHNS.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS drug product.
3. 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.
4. The patient has significant MPS IIIA behavioral-related issues, as determined by the Investigator, which would preclude performance of study neurocognitive and developmental testing procedures.
5. 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, such as condoms, barrier method, oral contraception, etc.
6. 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.
7. The patient has a history of poorly controlled seizure disorder.
8. 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.
9. 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.
10. The patient has received treatment with any investigational drug (other than rhHNS) 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).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
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 | EUCTR2010-021348-16-NL |
| CCMO | NL33810.018.11 |