E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mucopolysaccharidosis Type IIIA or Sanfilippo Syndrome |
MPS III is a progressive disorder that affects the brain and spinal cord , other systems may also be involved |
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E.1.1.1 | Medical condition in easily understood language |
Mucopolysaccharidosis Type IIIA (MPS IIIA) or Sanfilippo Syndrome |
MPS III is a progressive disorder that affects the brain and spinal cord , other systems may also be involved |
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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 | LLT |
E.1.2 | Classification code | 10028094 |
E.1.2 | Term | Mucopolysaccharidosis IH |
E.1.2 | System Organ Class | 100000004850 |
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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 |
Primary objective:
To evaluate the safety and tolerability of SOBI003 at different dose levels. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
1. To characterize tthe pharmacokinetics (PK) properties of SOBI003 following single and repeated administration by the use of non-compartmental analysis (NCA)
2. To assess the immunogenicity of SOBI003
3. To assess the pharmacodynamic (PD) effect of different dose levels and treatment duration of SOBI003 on heparan sulfate (HS) levels in
cerebrospinal fluid (CSF), serum and urine
4. To assess the effect of SOBI003 at different dose levels on neurocognition
5. To assess the effect of SOBI003 at different dose levels on adaptive behavior
6. To assess the effect of SOBI003 at different dose levels on gray matter volume
7. To assess the effect of SOBI003 at different dose levels on Quality of Life |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Patients/parents will optionally consent for future research and future genetic research. At Week 22, blood is collected for future genetic research. At Baseline and Week 22, blood and urine are collected for future biomarker research. CSF is collected at Baseline and Week 24 for future biomarker research. In case of Early Termination of SOBI003 treatment, blood and urine is collected for storage for future biomarker and genetic research. |
MPS IIIA is a very rare and severe disease for which there is a lot of research ongoing to further increase the understanding of disease pathology as well as diagnosis. The purpose of the sample storage is to allow future exploration/confirmation of new research findings. This includes:
SGSH genotypes
Geno- and/or phenotype associated correlations with possible impact on safety, tolerability, immunogenicity, PK and PD related to SOBI003 treatment
Biomarkers in serum, urine and/or CSF with possible relation to the safety, tolerability, immunogenicity, PK and PD of SOBI003 |
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E.3 | Principal inclusion criteria |
MPS IIIA patients, as confirmed by both a documented deficiency in sulfamidase enzyme activity in concordance with a diagnosis of MPS IIIA and normal enzyme activity level of at least one other sulfatase measured in leukocytes, that are ≥12 to ≤72 months of age and that have a developmental age ≥12 months.
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E.4 | Principal exclusion criteria |
Patients with at least one S298P mutation in the SGSH gene are excluded, as well as patients that have received prior stem cell or gene therapy, or enzyme replacement therapy for MPS IIIA. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events are recorded from the time of first investigational product administration until last study visit (Week 24).
Blood and urine samples for central laboratory analyses of hematology, clinical chemistry and coagulation are collected at Screening and prior to each infusion at Weeks 1 to 8. Pre-infusion sampling also applies biweekly from Week 10 to 22.
12-lead ECGs are obtained at Screening and prior to and post the infusions on Weeks 1 to 4, 6, 8, 12 and 24.
A physical examination will be performed at Screening, Baseline and at Week 24. General appearance and skin are examined prior to and within 1 hour of completion of each infusion. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints:
The secondary endpoints to evaluate the primary objective of the safety and tolerability of SOBI003 are:
- Vital signs (blood pressure, heart rate, body temperature, respiratory rate and oxygen saturation)
- Laboratory safety variables (hematology, coagulation, clinical chemistry and urine analysis)
The endpoints relating to the 1st secondary objective are:
- Serum SOBI003 PK parameters at Weeks 1, 4, 12, and 24; tEnd of inf,
CEnd of inf, Cmax, tmax, CPre-dose, CTrough, CL, AUC0-168h, t1/2
- CSF SOBI003 concentration at Weeks 12 and 24
The endpoints relating to the 2nd secondary objective are:
- Occurrence of anti-drug antibodies (ADAs) against SOBI003 in serum
(seroconversion rate, time to seroconversion, transient/persistent). For patients with confirmed ADA positive serum samples, the following additional endpoints apply; ADA titers and IgG subclasses in serum and presence of neutralizing antibodies (NAb) in serum.
- Occurrence of ADAs against SOBI003 in CSF (conversion rate, time to
occurrence, transient/persistent). For patients with confirmed ADA
positive CSF samples, the following additional endpoints apply; ADA
titers and presence of NAb in CSF.
The endpoints relating to the 3rd secondary objective are:
- Change from baseline in CSF HS at Weeks 12 and 24
- Change from baseline in serum HS at Weeks 2, 3, 4, 8, 12 and 24
- Change from baseline in urine HS at Weeks 2, 3, 4, 8, 12 and 24
The endpoints relating to the 4th secondary objective are:
- neurocognitive Development Quotient (DQ) and age-equivalence score (AEq) as assessed by the Bayley Scales of Infant and Toddler Development®, third edition (BSID-III)
- cognitive subtest or the Kaufman Assessment Battery for Children, Second edition (KABC™-II); change from baseline at Week 24.
The endpoint relating to the 5th secondary objective is
- adaptive behavior ageequivalence score (AEq) as assessed by Vineland™ Adaptive Behavior Scales, Expanded Interview Form, Second edition (VABS-II); change from baseline at Week 24.
The endpoint relating to the 6th secondary objective is gray matter volume as assessed by brain volumetric magnetic resonance imaging (MRI); change from baseline at Week 24.
The endpoint relating to the 7th secondary objective is Pediatric Quality of Life Inventory (PedsQL™) total score and PedsQL™ Family Impact Module total score; change from baseline at Week 24. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timespoints for evaluations:
- Serum concentration vs time profiles are obtained for determination of SOBI003 PK variables at Weeks 1, 4, 12 and 24.
- In addition, serum samples are collected when ADA samples are obtained. SOBI003 concentration in CSF is assessed at Weeks 12 and 24.
- HS is assessed in CSF at Baseline and Weeks 12 and 24.
- HS in serum at Baseline and at Weeks 2 to 4, 8, 12 and 24.
- HS in urine at Screening, Baseline, and at Weeks 2 to 4, 8, 12, and 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) | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
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 | 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 |
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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 | |
E.8.9.1 | In the Member State concerned months | 8 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |