Mucopolysaccharidosis III, type B (MPS IIIB), Sanfilippo B MedDRA version: 19.0 Level: LLT Classification code 10056918 Term: Sanfilippo's syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders MedDRA version: 19.0 Level: PT Classification code 10056890 Term: Mucopolysaccharidosis III System Organ Class: 100
Conditions
Sponsors
Alexion Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: A subject who meets all of the following inclusion criteria will be eligible to participate in this study: 1. Has a definitive diagnosis of MPS IIIB, as determined by either of the following: a. Documented deficiency in NAGLU enzyme activity =10% of the mean value in normal individuals (Heron, 2011, Am J Med 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 and less than 12 years old at the time of written informed consent, and has an age equivalent of =1 year on the Vineland II. 3. Has documented developmental delay with onset before 6 years of age, as defined by: a. Cognitive delay evaluated by BSID-III or KABC-II. OR b. Language delay, plateauing or regression of language skills as determined by the Investigator and confirmed by the Vineland-II (communication domain) administered at Screening (eg, subject uses isolated words, associated words such as two-word combination, sentences, poor or reduced language and/or language difficult to understand). 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 urinepregnancy 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 last dose of SBC-103. Women may be considered of non-childbearing potential if they have not started their menses or are surgically sterile (ie, 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. Part B Qualifications for Participation in Part B (Therapy at 1 and/or 3 mg/kg) Subjects are eligible for continued SBC 103 dosing in Part B if they do not meet any Exclusion criteria and if they meet the following: 1. Completion of Part A with no unmanageable study drug toxicity; 2. Continue to meet Inclusion Criteria items 4-7; and 3. SRC and Sponsor have reviewed the subject’s safety data from Part A and have deemed it acceptable for the subject to re-initiate dosing in Part B.
Exclusion criteria
Exclusion criteria: A subject who meets any of the following exclusion criteria will be ineligible to participate in this study: 1. Received treatment with gene therapy at any time, or any investigational drug (including high dose genistein > 150 mg/kg/day), 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. 2. 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 an MRI is contraindicated according to local institutional policy. 3. Previous hematopoietic stem cell or bone marrow transplant. 4. Known or suspected hypersensitivity to anesthesia or the use of a sedative is contraindicated for any other reason. 5. History of poorly controlled seizure disorder. 6. 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. 7. Known hypersensitivity to eggs. Subjects at high risk for food allergy that may include eggs should be tested according to local guidelines. 8. Other medical conditions or co-morbidities (eg, ALT or AST > 3x ULN, confirmed by repeat testing, analyzed centrally or locally and based on the standardized reference range provided in the central laboratory manual), or other markers of clinically significant liver dysfunction (eg. elevated bilirubin, [with the exception of patients with confirmed Gilberts Disease] confirmed by repeat testing, or elevated prothrombin time [PT]P/ International normalized ratio [INR] confirmed by repeat testing analyzed centrally or locally and based on the standardized reference range provided in the central laboratory manual) which in the opinion of the Investigator, in consultation with the Sponsor, would interfere with study compliance, or confound data interpretation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of the IV administration of SBC-103 in subjects with mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) with evaluable signs or symptoms of developmental delay.;Timepoint(s) of evaluation of this end point: Every two weeks; Secondary Objective: • To characterize the PK profile of SBC-103 administered IV. • To determine the effects of SBC-103 administered IV on the levels, onset and magnitude of changes in total HS in CSF, serum, and urine. • To evaluate the PD/efficacy of doses of SBC-103 administered IV as measured by neurocognitive and developmental function and change in brain structures. • To evaluate the impact of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, tolerability, and select PD/efficacy markers, including the reversibility of changes in levels of total HS in CSF, serum, and urine. ; Primary end point(s): 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 (IAR)s; • Changes from baseline in clinical laboratory tests (hematology, serum chemistry, and urinalysis) and CSF findings (cell counts, glucose, and protein); • Changes from baseline in 12-lead electrocardiograms (ECGs) ; • Changes in vital signs during and post-infusion, relative to pre-infusion values; • Physical examination findings; • Use of concomitant medications/therapies; • Assessment of ADAs, including seroconversion rate, time to seroconversion, and ADA titer by time point, peak ADA titer, and ADA titer status (positive/negative), and the effect of ADAs on the safety of SBC-103, | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints of this study are baseline and post-treatment measures of the following assessments: • PK profile of SBC-103 after single and multiple doses: - Maximum observed serum concentration (Cmax) - Time to reach Cmax (Tmax) - Area- under- the- concentration-time -curve from time 0 to the last measurable time point (AUClast) - Area-under-the-concentration-time curve extrapolated to infinity (AUC8) - Half-life (T1/2) - Clearance (CL) - Volume of distribution at terminal phase (Vz) - Accumulation ratio (Rac) • Effects of SBC-103 treatment on the onset, magnitude, and reversibility of changes in levels of total HS in CSF, serum, and urine. • Neurocognitive and developmental function as determined by the scores on Vineland Adaptive Behavior Scales, Second Edition (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. • Effect of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, tolerability and select PD/efficacy markers Exploratory endpoints in this study include measures to examine the onset, magnitude, and reversibility of changes in exploratory biomarkers, SBC-103 concentration in CSF, MPS IIIB disease characteristics, symptoms, and QOL after IV administration of SBC- | — |
Countries
Spain, United Kingdom, United States
Contacts
Public ContactEuropean Clinical Trial Information
Alexion Europe SAS
Outcome results
None listed