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 |
•Evaluate the long-term safety and tolerability of AX 250 administered to subjects with MPS IIIB by an implanted ICV reservoir and catheter • Evaluate the impact of long-term AX 250 treatment 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 |
• Evaluate the impact of long-term AX 250 treatment on cognitive function in patients with MPS IIIB as assessed by age equivalent score (AEq) • Characterize immunogenicity of long-term AX 250 treatment in CSF and serum • Evaluate the impact of long-term AX 250 treatment on CSF, serum and urine GAGs • Evaluate the impact of long-term AX 250 treatment on brain structure assessed by magnetic resonance imaging (MRI) • Evaluate the impact of long-term 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 |
•Must have completed 48 weeks in Part 2 of Study 250-201 and enter 250-202 within 8 weeks of study completion • 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 • Males and females who are of reproductive age should practice true abstinence, defined as no sexual activity, during the study and for 6 months after the study has been completed (or withdrawal from the study). If sexually active and not practicing true abstinence, males and females of reproductive age must use a highly effective method of contraception while participating in the study. • 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 250-201 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 • 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 other than AX 250 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 lon-term safety and tolerability of AX 250 administered to subjects with MPS IIIB by an implanted intracerebroventricular (ICV) reservoir and catheter.
To evaluate the lon-term impact of AX 250 treatment 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 evaluation will include continuous monitoring of AEs and concomitant medications. Clinical laboratory assessments at Baseline and every 4W the first 96W, Q12W thereafter. CSF for cell count, protein, and glucose collected prior to each weekly infusion. A complete physical examination performed at Baseline and every 24W thereafter. The exam includes assessment of general appearance, vital signs, measurements of height, weight and head circumference, a detailed neurological examination, and assessment of cardiovascular, respiratory,and gastrointestinal systems. Brief physical exams weekly dosing visits when complete exams are not performed. ECG and EEG performed at the EoT. Brain imaging (MRI or CT) to monitor for asymptomatic subdural hygroma formation at a frequency of up to Q4W |
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E.5.2 | Secondary end point(s) |
The secondary objectives of this study are: *to evaluate the long-term impact of AX 250 treatment 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 long-term AX 250 treatment 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 (VABSII). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The CSF, as well as blood collected at less frequent intervals, will be used for GAG analyses and/or exploratory analyses of the biochemical, molecular, cellular and genetic/genomic aspects of MPS IIIB.
CSF and blood (serum) will be drawn throughout the study to analyze immunogenicity
Urine will be collected for GAG and creatinine analyses as well as for exploratory analyses at Baseline and every 24 weeks thereafter.
Brain structure will be evaluated by MRI during Baseline visits and at Weeks 24 and 48. |
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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) | 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) | 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 |
Colombia |
Germany |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |