To evaluate the safety and tolerability of IV administration of SBC-103 in subjects with MPS lllB, Sanfilippo B.
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study is safety and tolerability of SBC-103 in
subjects with MPS IIIB. The safety assessments will include the following:
* Incidence of AEs, serious adverse events (SAEs), and
infusion-associated reactions (IARs);
* Clinical laboratory tests (hematology,
serum chemistry, and urinalysis) and CSF findings (cell counts,
glucose, and protein);
* 12-lead electrocardiograms (ECGs);
* Vital signs during and post-infusion, relative to
pre-infusion values;
* Physical examination findings;
* Use of concomitant medications/therapies;
* Assessment of anti-drug antibodies (ADAs,)(positive/negative) including
ADA titer for the samples with confirmed positive ADA status and the effect of
ADAs on the safety of
SBC-103, including the relationship between ADA-positive subjects and the
incidence of IARs, including hypersensitivity reactions.
Secondary outcome
Serum PK parameters for unlabeled SBC-103 after single and multiple doses:
* Maximum observed serum concentration (Cmax)
* Time to reach Tmax
* Area-under-the-concentration-tim curve from time 0 to the last measurable
time point (AUC*)
* Area-under-the-concentration-time curve extrapolated to
infinity (AUC*)
* Half-life (T1/2)
* Clearance (Cl)
* Volume of distribution at terminal phase (Vz)
* Accumulation ratio (Rac)
* Plasma and tissue PK parameters for 89Zr-SBC-103, as appropriate
* Quantitative assessment of 89Zr-SBC-103 in Regions of
Interest (ROI) in the central nervous system (CNS) based on
images after single dose administration as measured by
Standardized Uptake Value (SUV) and its conversion to drug
concentration.
* Quantitative assessment of 89Zr-SBC-103 values in images
of the major organs of the body (including liver, heart and
spleen) after single dose administration as measured by SUV
and drug concentration.
* Direct radiolabel counting and assessment of NAGLU
enzyme activity contained in blood samples (Day 0 pre-,
during, and post-infusion) to characterize the plasma PK
profile following IV dosing of SBC-103.
* Relationship between the serum drug
concentration, unlabeled SBC-103, and drug concentrations
of radiolabeled SBC-103 in the brain and other major organs
(including liver, heart and spleen).
* Effects of SBC-103 administered IV on levels of total HS in CSF,
serum, and urine.
* Neurocognitive and developmental function as determined by
the scores on the Vineland-II and, as appropriate to the subject*s
age, the Bayley Scales of Infant and Toddler Development,
Third Edition (BSID-III) or Kaufman Assessment Battery for
Children, Second Edition (KABC-II), Bruininks-Oseretsky
Test of Motor Proficiency, Second Edition, Brief Form
(BOT-2 Brief Form), and Children*s Communication
Checklist, Second Edition (CCC-2).
* Brain structure as determined by the relative proportion of
grey and white matter volume and indices of microstructural
integrity as assessed by MRI of the brain.
Background summary
Mucopolysaccharidosis type IIIB (MPS IIIB), also known as Sanfilippo B
Syndrome, is a rare disease that causes build-up of sugars (heparan sulfate) in
the brain and other parts of the body. This is due to the lack of the enzyme
called NAGLU (or N-acetylglucosaminidase). The build-up causes serious health
problems that include changes in behaviour, mental retardation and severe
physical disability. There are currently no approved treatments for MPS IIIB.
In studies with animals that also lack the NAGLU enzyme, the investigational
drug SBC-103 has been shown to reduce the build-up of sugars in the brain and
liver of these animals. The study will help provide information on whether
similar reduction of sugars can be observed in subjects with MPS IIIB. The
purpose of this study is to investigate whether delivering this missing enzyme
to the brain will help to stop or slow down the progression of the disease and
to learn more about the safety and tolerability of intravenous (IV)
administration of SBC-103.
Study objective
To evaluate the safety and tolerability of IV administration of SBC-103 in
subjects with MPS lllB, Sanfilippo B.
Study design
Three dose levels (3, 5, or 10 mg/kg) will be investigated in this study.
Patient will receive one of these dose levels, administered by an intravenous
(IV) infusion once every other week for up to 156 consecutive weeks (3 years) .
The first subject entering the study will receive the low dose , while the
third subject entering the study will receive the high dose. The fourth subject
entering the study will receive 3,5 or 10 m/kg.
Intervention
SBC-103 is rhNAGLU manufactured using transgenic Gallus, which produce
rhNAGLU in egg white. 89Zr-SBC-103 is radiolabeled rhNAGLU prepared
from sterile SBC-103 labeled with 89Zr using established methodology for
radiolabeling of proteins.
Study burden and risks
After finalization of the screeningstests for testing if patient is eligible
for participation, the patient will visit the hospital every 2 weeks for 156
weeks. During these visits the following procedures will take place:
- physical examination 41 times
- photography face 6 times
- questionnaires 6 times
- ECG 9 times
- lumbar puncture 14 times
- overall anesthesia 14 times
- MRI 5 times
- PET/CT scan 1 time
Please refer to protocol section 14.1-14.3 as well for an overview of the
procedures.
Please refer to E9.
Knotter Drive 352
Cheshire CT 06410
US
Knotter Drive 352
Cheshire CT 06410
US
Listed location countries
Age
Inclusion criteria
1.Has a definitive diagnosis of MPS IIIB, as determined by either of the
following:
a.Documented deficiency in alpha-N-acetylglucosaminidase (NAGLU)
enzyme activity * 10% of the mean value in normal individuals (Heron, 2011, Am J Met Genet A) based on test results from a central laboratory
at Screening.
OR
b.Documented functionally-relevant mutations in both alleles of the
NAGLU gene based on historical test results from a local laboratory (if
available) or results from the central laboratory at Screening.
2.Greater than or equal to 2 years old at the time of written informed
consent, and has an age equivalent of * 1 year on the Vineland Adaptive
Behavior Scales, Second Edition (Vineland II).
3.Subject weight is * 30 kg.
4.Subject or subject's parent or legal guardian (if applicable) consents to
participate in the study and provides informed consent prior to any study
procedures being performed. If the subject is of minor age; he/she is
willing to provide assent where required per local regulations, and if
deemed able to do so.
5.Female subjects who are of childbearing potential at the time of
consent or who become of childbearing potential during participation on
study (a) must have a negative urine pregnancy test at Screening, (b)
cannot be breast feeding, and (c) must consent to use a highly reliable method of
birth control (expected failure rate less than 5% per year) for the
duration of the study and for 30 days after the last dose of SBC 103. Women
may be considered of non-childbearing potential if they have not started
their menses or are surgically sterile (i.e., total hysterectomy or bilateral
salpingo-oophorectomy).
6.Male subjects must consent to use a highly reliable method of birth control
(expected failure rate less than 5% per year) during any sexual contact
with females of childbearing potential while participating in the study
and for 30 days following discontinuation from this study even if he has
undergone a successful vasectomy.
7.Willingness and ability to comply with protocol requirements to the
extent that may be expected of a subject with cognitive impairment.
Exclusion criteria
1.Has any other medical condition or circumstance in which a
PET/CT scan is contraindicated according to
local institutional policy.
2.Prior exposure to radiation which,
3.Received treatment with gene therapy at any time, or any
investigational drug or
device intended as a treatment for MPS IIIB within 30 days prior to
Screening, or is currently being treated in another study that involves an
investigational drug or device.
4.Has any internal or non-removable external metal items that may
present a safety risk for study assessments that utilize magnetic fields,
or any other medical condition or circumstance in which magnetic
resonance imaging (MRI) is contraindicated according to local
institutional policy.
5.Previous hematopoietic stem cell or bone marrow transplant.
6.Known or suspected hypersensitivity to anesthesia or the use of a
sedative is contraindicated for any other reason.
7.History of poorly controlled seizure disorder.
8.A bleeding disorder, or any other medical condition or circumstance in
which a lumbar puncture (for collection of CSF) is contraindicated
according to local institutional policy.
9.Known hypersensitivity to eggs. Subjects at high risk for food allergy
that may include eggs should be tested according to local guidelines.
10.Other medical conditions or co morbidities (eg, alanine
aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 x
the upper limit of normal (ULN), confirmed by repeat testing), or other
markers of clinically significant liver dysfunction (eg, elevated bilirubin,
[with the exception of subjects with confirmed Gilberts Disease]
confirmed by repeat testing, or elevated prothrombin time
[PT]/international normalized ratio [INR] confirmed by repeat testing),
which in the opinion of the Investigator, in consultation with the
Sponsor, would interfere with study compliance, or confound data
interpretation.
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 | EUCTR2015-000753-20-NL |
| CCMO | NL52845.029.15 |