E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
MPS IIIB is a devastating lysosomal storage disease, caused by a N-α-acetylglucosaminidase (NAGLU) gene defect. Infants with MPS IIIB appear normal at birth, but the disease is relentlessly progressive, with deterioration of social and adaptive abilities, neurocognitive decline, and premature death. Death typically occurs by end of the second or beginning of the third decade. Quite importantly, there is no treatment currently available for the disease. |
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E.1.1.1 | Medical condition in easily understood language |
Mucopolysaccharidosis type IIIB is a genetic disease in children, caused by the toxicity of an accumulation of substances in the body that generate a progressive deterioration. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
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 |
Primary outcomes of safety and initial efficacy |
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E.2.2 | Secondary objectives of the trial |
1. Reduction of CSF, plasma or urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment
2. Increase in CSF or plasma NAGLU enzyme activity levels at 6 and/or 12 months after treatment
3. Reduced liver and/or spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI)
4. Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months after treatment, as assessed by parent report using the Vineland Adaptive Behavior Scale II
5. Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Leiter International Performance Scale (brief IQ), the Mullen Scales of Early Learning; and by parent report using the Sanfilippo Behavior Rating Scale
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 6 months old or greater
2. Confirmed diagnosis of MPS IIIB by both of the following methods:
a. No detectable or significantly reduced NAGLU enzyme activity by plasma, serum, or leukocyte assay.
b. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene
3. Clinical history or examination features of neurologic dysfunction
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E.4 | Principal exclusion criteria |
1. Inability to participate in the clinical evaluation as determined by principal investigator
2. Identification of two nonsense or null variants on genetic testing of the NAGLU gene, as judged by the principal investigator
3. Prior treatment with NAGLU enzyme replacement therapy (ERT)
4. Has evidence of an attenuated phenotype of MPS IIIB, as judged by the principal investigator
5. Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
6. Inability to be safely sedated in the opinion of the clinical anesthesiologist
7. Active viral infection based on clinical observations
8. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
9. Subjects with anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
10. Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
11. 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
12. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
13. Uncontrolled seizure disorder, due to the requirement for multiple MRI examinations as part of the study protocol. Subjects who are stable on anticonvulsive medications may be included
14. Any item (braces, etc.) which would exclude the patient from being able to undergo MRI according to local institutional policy
15. Any other situation that would exclude the patient from undergoing any other procedure required in this study
16. Subjects with cardiomyopathy or significant congenital heart abnormalities
17. The presence of significant non-MPS IIIB related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
18. Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.0 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
19. Female participant who is pregnant or demonstrates a positive urine or β-HCG result at screening assessment (if applicable).
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E.5 End points |
E.5.1 | Primary end point(s) |
Determination of safety based on the development of unacceptable toxicity: defined as the occurrence of two or more unanticipated Grade III or higher treatment-related toxicity |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events will be evaluated along the entire trial during 24 months |
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E.5.2 | Secondary end point(s) |
1. Reduction of CSF, plasma or urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment
2. Increase in CSF or plasma NAGLU enzyme activity levels at 6 and/or 12 months after treatment
3. Reduced liver and/or spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI)
4. Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months after treatmnt, as assessed by parent report using appropiate scale.
5. Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child and by parent report using the appropiate scales. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Day -45 to -1 (patient inclusion); day 1, 7, 14, 30, 60, 90, 180, month 12, month 18, month 24
- Day -45 to -1 (patient inclusion); day 7, 14, 30, 60, 90, 180, month 12, month 18, month 24
- Day -45 to -1 (patient inclusion); days 30, 180, month 12, month 24
- Day -45 to -1: day 180, month 12, month 18, month 24
- Day -45 to -1: day 180, month 12, month 18, month 24 |
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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 | 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 | 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 | No |
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 | 7 |
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 |
France |
Germany |
Italy |
Netherlands |
Spain |
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 | 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 |