E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Sanfilippo Syndrome Type A or Mucopolysaccharidosis (MPS IIIA) |
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E.1.1.1 | Medical condition in easily understood language |
Sanfilippo Syndrome Type A or Mucopolysaccharidosis (MPS IIIA) |
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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 | 14.0 |
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 | 14.0 |
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 |
To determine the safety and tolerability of rhHNS via ascending doses administered via a surgically implanted intrathecal drug delivery device (IDDD) once monthly or every other week (EOW) for 6 months, in patients with MPS IIIA. |
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E.2.2 | Secondary objectives of the trial |
•To determine by dose group the effects of IT administration of rhHNS, as measured as (1) change from baseline values, and (2) comparison to values obtained in a longitudinal, 12 month, natural history study of untreated patients with MPS IIIA in the Shire HGT SAN 053 Surrogate Endpoint Trial, on the following measurements/assessments over a 6 month period:
•Standardized neurocognitive and behavioral assessments
•Concentration of rhHNS in cerebrospinal fluid (CSF) and serum.
•Concentration of safety/potential surrogate efficacy biomarkers in CSF, urine, and serum.
•Concentration of heparan sulfate and heparan sulfate derivatives in urine and CSF
•Brain MRI and auditory brainstem response |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. a.)Patients have a documented deficiency in sulfamidase enzyme activity of ≤10% of the lower limit of the normal range as measured in fibroblasts or leukocytes (based on measurements by a laboratory that is acceptable to Shire HGT).
AND EITHER b or C
b.)Patients have a normal enzyme activity level of at least 1 other sulfatase (to rule out multiple sulfatase deficiency) as measured in fibroblasts or leukocytes (based on measurements by a laboratory that is acceptable to Shire HGT).
c.) Patients have 2 documented mutations (based on assessments by a laboratory that is acceptable to Shire HGT).
2. The patient is ≥3 years of age and has a developmental age above 1 year (developmental age will be determined by the screening neurocognitive and developmental tests).
3. Patients must be medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery, without placing an undue burden on the patient/patient's family.
4. The patient’s parent(s) or legal guardian must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form |
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E.4 | Principal exclusion criteria |
1. The patient has significant non-MPS IIIA related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the Investigator.
2. The patient has MPS IIIA behavioral-related issues, as determined by the Investigator that would preclude performance of study neurocognitive and developmental testing procedures.
3. The patient is pregnant, breast feeding, or is a female patient of childbearing potential who will not or cannot comply with the use of an acceptable method of birth control
4. The patient is blind and/or deaf
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions.
6. The patient or the patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
7. The Investigator may choose to exclude patients who have had complications resulting from prior lumbar punctures.
8. The patient has a CNS shunt.
9. The patient has skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
10. The patient has a history of poorly controlled seizure disorder.
11. The patient is currently receiving psychotropic or other medications, which in the Investigator’s opinion, would be likely to substantially confound test results and the dose and regimen of which cannot be kept constant throughout the study.
12. The patient cannot sustain absence from aspirin, non-steroidal medications, or medications that affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device implantation if applicable), or has ingested such medications within 1 week before any procedures in which any change in clotting activity would be deleterious.
13. The patient has received treatment with any investigational drug or a device intended as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently enrolled in another study that involves an investigational drug or device (screening through safety follow-up contact).
14. The patient has received a hematopoietic stem cell or bone marrow transplant.
15. The patient’s parent(s), or patient’s legal guardian(s) is/are unable to provide consent or the patient cannot provide assent, |
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E.5 End points |
E.5.1 | Primary end point(s) |
To determine the safety of intrathecal rhHNS administration, as measured by adverse events (by type and severity), changes in clinical laboratory testing (serum chemistry including liver function tests, hematology, and urinalysis), electrocardiograms, CSF chemistries (including cell counts and inflammatory markers), and anti-rhHNS antibodies (in CSF and serum).
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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) |
•To determine (by dose group) the effects of IT administration of rhHNS, as measured by (1) change from baseline values, and (2) comparison to values obtained in a natural history study of untreated patients with MPS IIIA Surrogate Endpoint Trial ◦Neurocognitive/behavioral tests
◦Gross and fine motor skills assessment
◦QoL
◦rhHNS levels, inflammatory cytokines, heparan sulfate levels (including derivatives) and biomarkers
◦MRI
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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 | No |
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 | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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Last visit of the last patient in the clinical study. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |