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 | 20.0 |
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.1.2 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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 on cognitive function in patients with MPS IIIB as assessed by development quotient (DQ). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the impact of AX 250 on cognitive function in patients with MPS IIIB as assessed by age equivalent score (AEq).
To characterize single- and repeated-dose pharmacokinetics (PK) of AX 250 in cerebrospinal fluid (CSF) and plasma.
To characterize immunogenicity of AX 250 in CSF and serum.
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 MRI.
To evaluate the impact of AX 250 treatment on adaptive function derived from the Vineland Adaptive Behavior Scales, 2nd edition (VABS-II). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part 1: Dose Escalation Period:
Has deficient NAGLU enzyme activity at Screening. Blood for NAGLU enzyme activity will be collected and analyzed centrally.
Is ≥ 1 and <11 years of age (at least 1 of the 3 subjects in Part 1 must be >1 and <6 years of age).
Has presented with signs/symptoms consistent with MPS IIIB; for individuals who have not presented with signs/symptoms of the disease (e.g., siblings of known patients), the determination of eligibility will be at the discretion of the Allievex medical monitor in conjunction with the site investigator.
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.
Part 2: Stable Dose Period:
Participated in and met protocol requirements for transitioning from Study 250-901 or participated in Part 1 of Study 250-201
Written informed consent from parent or legal guardian and assent from subject, if required
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E.4 | Principal exclusion criteria |
Part 1: Dose Escalation Phase:
Has received stem cell, gene therapy, or enzyme replacement therapy for MPS IIIB.
Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities).
Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain).
Has a history of poorly controlled seizure disorder.
Is prone to complications from intraventricular 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.
Is pregnant at any time during the study
Part 2: Stable Dose Period: Has received stem cell, gene therapy or ERT for MPS IIIB
Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities)
Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain)
Is prone to complications from intraventricular 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.
Is pregnant at any time during the study
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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 on cognitive function in patients with MPS IIIB as assessed by developmental quotient (DQ). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety + tolerability reviews: monitoring of AEs +concomitant medic.; clinical lab assess. at Screening, prior to/day after 1st dose at each dose level and Q4W until next dose escalation in Pt.1 + Screening, prior to/day after 1st dose + Q4W thereafter in Pt.2;CSF for cell count, protein, glucose collected prior to weekly infusions; pre/post-dose blood samples for serial PK analysis monitored for glucose level; complete physical exam at Screening, Baseline and dose escalation visits in Pt.1 and Baseline and Wks 24 and 48 . in Pt.2,phys. exams at weekly dosing visits when complete exams not performed; ECG+ EEG at Screening +EoS of study. Brain imaging to monitor asymptomatic subdural hygroma formation up to Q4W. Neurocognitive tests :Baseline in Pt.1 - Baseline, Wks 12, 24, 36, 48 in Pt.2. |
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E.5.2 | Secondary end point(s) |
The secondary objectives of this study are: *to evaluate the impact of AX 250 on cognitive function in patients with MPS IIIB as assessed by age equivalent score (AEq) *to characterize single- and repeated-dose pharmacokinetics (PK) of AX 250 in cerebrospinal fluid (CSF) and plasma *to characterize immunogenicity of AX 250 in CSF and serum *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) *To evaluate the impact of AX 250 treatment on adaptive function derived from the Vineland Adaptive Behavior Scales, 2nd edition (VABS-II). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
VABS-II/Neurocognitive tests (from which AEq is derived) at Baseline in Part1, and Baseline, Weeks 12, 24, 36, 48 in Part2.
Sampling of CSF and blood (plasma) for serial PK and GAG analyses will be following the first dose and subsequent dose escalations in Part1 and for doses at Baseline, and Weeks 5, 12 and 36 in Part2. CSF and blood (plasma) samples will also be used for trough PK performed Q4W in Part2.
CSF and serum will be drawn throughout the study to analyze immunogenicity.
Urine will be collected for GAGs/creatinine analysis prior to initial dosing at each dose level and Q4W until the next dose escalation in Part1, and Baseline and Q4W thereafter in Part2.
Brain structure will be evaluated by MRI during Part1 and Part2 Baseline visits and at Weeks 24 and 48 in Part2.
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | Yes |
E.8.2.3.1 | Comparator description |
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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 | 3 |
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 |
Australia |
Colombia |
Germany |
Spain |
Taiwan |
Turkey |
United Kingdom |
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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 | 2 |
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 | 2 |
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 |