E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
MPS IIIA, mucopolysaccharidosis type IIIA |
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E.1.1.1 | Medical condition in easily understood language |
Sanfilippo Syndrome type A |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
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 | 10028093 |
E.1.2 | Term | Mucopolysaccharidosis |
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 |
1) To evaluate the safety and tolerability of the IMP in patients with MPS IIIA. The study will include safety measures for immunosuppressed individuals post HSCT to monitor conditioning regimen related toxicity and haematological reconstitution as well as those related to the IMP
2) To evaluate biological efficacy of the IMP post treatment as primarily measured by peripheral expression of SGSH activity in total leukocytes |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate overall survival
2) To evaluate peripheral engraftment of the IMP
3) To evaluate clinical efficacy on cognitive function as assessed by standard scores, age equivalent scores and development quotient (DQ)
4) To evaluate the impact of the IMP on patient behaviour, adaptive function, QoL and the impact of treatment on parents or caregivers |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of written informed consent prior to any study related procedures. This study consent must be provided by the parents/legal guardians
2. Age at baseline ≥3 months and ≤24 months
3. Normal cognitive function or mild cognitive deterioration at baseline (Development Quotient ≥80) as determined by the Bayley Scale of Infant Development-third edition (BSID-III), cognitive domain, or assessed as normal or only mildly impaired by experienced neuropsychologist and agreed by independent expert reviewer
4. Sibling or relative of known MPS IIIA patients with rapidly progressing phenotype or genotype associated with rapidly progressing phenotype or presence of somatic features predictive of rapid progression (including but not limited to mild facial dysmorphism, frequent ear infections, frequent upper respiratory infections, umbilical/inguinal hernia, diarrhoea, speech delay, sleeping difficulties, hyperactivity, attention deficit and hearing difficulties, early behavioural problems including perseverative chewing and difficulty with toilet training)
5. Diagnosis of MPS IIIA based on evidence of SGSH deficiency, defined as Sulfoglucosamine Sulfohydrolase (SGSH) activity ≤10% of the Lower Limit of Normal as measured in total leukocytes, plus either (1) a normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leukocytes, or (2) two documented mutations in the SGSH gene
6. Medically stable and able to accommodate the protocol requirements (including travel) and protocol assessments without placing an undue burden on the subject/subject’s family, as determined by the CI
7. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to commit to attend clinic for the required duration during the study and follow up period as specified in the protocol |
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E.4 | Principal exclusion criteria |
1. The subject has previously received stem cell therapy, gene therapy or enzyme replacement therapy (any route of administration)
2. Subject currently enrolled in other interventional trial
3. Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain)
4. The subject has a history of poorly controlled seizures
5. Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow progressing phenotype
6. The patient is currently receiving psychotropic or other medications which, in the CI’s opinion, would be likely to substantially confound test results
7. The patient has received any investigational medication (including Genistein) within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study
8. Documented Human Immunodeficiency Virus (HIV) infection (positive HIV ribonucleic acid [RNA] and/or anti p24 antibodies)
9. Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome. Subjects with a prior successfully treated malignancy and a sufficient follow up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Medical Monitor
10. Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia, or other serious haematological disorders
11. Medical condition or extenuating circumstance that, in the opinion of the CI 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
12. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
13. Severe behavioural disturbances due to reasons other than MPS IIIA and likely to interfere with protocol compliance, as determined by the CI
14. Known sensitivity to busulfan
15. The receipt of live vaccinations within 30 days prior to study start |
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E.5 End points |
E.5.1 | Primary end point(s) |
A demonstration of normal or above normal SGSH activity in total leukocytes 12 Months post-IMP treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Change in cognitive scores (standard scores, age equivalent scores and development quotient) measured using the Bayley Scales of Infant Development, 3rd Edition [BSID III] or Kaufman Assessment Battery for Children, 2nd Edition [KABC II] at 36 months post IMP treatment and multiple visits over time according to the schedule of assessments
For subjects reaching the developmental age ceiling of the BSID III (42 months), the KABC II will be administered. Transition between neurocognitive scales will be done by overlapping both tests from visit prior to reaching a developmental age of 42 months and continue with both tests, if at all possible, for as many visits as possible. When both tests are administered, tests will be performed in two consecutive days per visit.
The choice of the appropriate test for developmental assessment will be made using the algorithm provided in Appendix 3: Cognitive assessment algorithm
Measurement of the proportion of cells containing the inserted SGSH gene in total leukocytes at multiple visits over time Evaluation of VCN in total leukocytes at multiple other visits over time Change from baseline in SGSH activity in total leukocytes at 3 months post treatment and at multiple other visits over time Change in adaptive behaviour measured using the Vineland Adaptive Behaviour Scales, 2nd Edition (VABS II) at multiple visits over time Change in subject’s behaviour and activities of daily living measured using: o Sanfilippo Behaviour Rating Scale (SBRS) o Infant Toddler Quality of Life questionnaire (ITQoL) o Children Sleep Questionnaire (CSHQ) o Child Health Assessment Questionnaire (CHAQ) Change in parent/caregiver QoL, measured using: o Parenting Stress Index (Overall level of parenting stress experienced by parents of children) o Beck Depression Inventory, second edition. o Paediatric QoL Inventory (PedsQL) Family Impact Module |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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) | 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 | 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.8.3 |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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Each subject’s participation in the study will have ended at the time of his/her last visit, withdrawal of consent or death. The study will have ended after the last subject has completed the last study visit at 36 months post-IMP treatment. |
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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 | |
E.8.9.1 | In the Member State concerned days | |