E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome Type B, MPS IIIB) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10056890 |
E.1.2 | Term | Mucopolysaccharidosis III |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056918 |
E.1.2 | Term | Sanfilippo's syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- Further evaluate the long-term safety and tolerability of AX 250 administered by an implanted ICV device to subjects with MPS IIIB who have completed AX 250-202. - Further evaluate the impact of long-term AX 250 treatment on various skills and function as assessed in patients with MPS IIIB who have completed AX 250-202 |
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E.2.2 | Secondary objectives of the trial |
- to Characterize immunogenicity of AX 250 in CSF and serum - to evaluate the impact of AX 250 treatment on cognitive function in patients with MPS IIIB as assessed by development quotient (DQ) - to evaluate the impact of AX 250 treatment on CSF, serum and urine GAGs - to evaluate the impact of AX 250 treatment on brain structure assessed by magnetic resonance imaging (MRI)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible to participate individuals must meet all of the following criteria: - Must have completed 240 weeks of study 250-202 and enter study 250-401 with the first infusion occurring within 8 weeks of completing study 250-202. - Provided written informed consent from parent or legal guardian and assent from subject, if required. - Has the ability to comply with protocol requirements, in the opinion of the investigator. - If female with childbearing potential, must have a negative pregnancy test at the Screening visit and be willing to have additional pregnancy tests during the study. |
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E.4 | Principal exclusion criteria |
Individuals who meet any of the following exclusion criteria are ineligible to participate in this study: - Has (1) a cognitive AEq score ≤ 18 months, (2) a DQ score ≤ 20, and (3) no evidence of improvement during the 250-202 study in secondary or exploratory efficacy endpoints. - Would not benefit from enrolling in the study in the opinion of the investigator. - Has received stem cell, gene therapy or ERT (other than AX 250) for MPS IIIB since completing Study 250-202 prior to starting Study 250-401. - Has a history of poorly controlled seizure disorder. - Is prone to complications from ICV drug administration including patients with hydrocephalus or ventricular shunts. - Has received any investigational medication within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study. - Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with protocol requirements, the subject’s well-being or safety, or the interpretability of the subject’s clinical data. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- To evaluate the safety and tolerability of AX 250 administered to subjects with MPS IIIB by an implanted intracerebroventricular (ICV) reservoir and catheter. - To evaluate the impact of AX 250 treatment on cognitive function in patients with MPS IIIB as assessed by age equivalent score (AEq). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety evaluation includes -continuous monitoring of AEs and concomitant medications -complete physical examination (prior to 1º dose and Q24W thereafter through W144/Dosing Completion) includes an assessment of general appearance,cardiovascular,dermatologic,lymphatic,respiratory,gastrointestinal,genitourinary,musculoskeletal,neurologic systems and measurements of body weight,height and head circumference -brief physical exams are performed at dosing visit when complete physical exams not performed -clinical laboratory assessments at Baseline and Q24W thereafter -ECG and EEG performed at Screening/Baseline and at EoD or EoT -Brain imaging (MRI or CT) to monitor for asymptomatic subdural hygroma formation Efficacy evaluation includes -Neurocognitive testing using BSID-III or KABC-II |
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E.5.2 | Secondary end point(s) |
- Secondary Efficacy evaluation includes: -- measures of communication assessment (BSID-III) -- measures of communication, motor skills and socialization skills as determined by VABS-II testing -- quality of life by ITQoL or CHQ-PF50 - Liver and spleen volumes assessed by abdominal magnetic resonance imaging (MRI) - Regional brain volumes assessed by brain MRI - Pharmacodynamic Biomarkers: Glycosaminoglycans (GAGs) - Immunogenicity tests (validated immunogenicity assays on serum and CSF samples)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- VABS-II , ITQOL or CHQ-PF50, MRI (under anesthesia) of the brain and abdomen performed every 48 weeks (± 2 weeks). - GAG: -- serum Week 4, Q4W thereafter -- plasma Week 12, Q12W thereafter - Immunogenicity tests : Samples of serum for TAb and CSF for TAb and NAb collected Q48W through Week 144/Dosing Completion. Samples of serum for NAb collected prior to the first dose and Q48W through Week 144/Dosing Completion. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Colombia |
United Kingdom |
United States |
Germany |
Türkiye |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |