enzyme impairment - Lysosomal disorder
Conditions
Interventions
IMP administration will be performed by peripheral intravenous access using a
commercially available infusion pump and devices that have been designed for
administration of intravenous medications a
adeno-associated viral vector (AAV)
ARSB gene
Gene Therapy
Mucopolysaccharidosis
Sponsors
Fondazione Telethon
Eligibility
Age
2 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Subjects must have a documented biochemical and molecular diagnosis of MPS VI. 2. Subjects must be 4 years old or older. 3. Subjects should have received Enzyme Replacement Therapy (ERT) for at least 12 months before enrolment, and should continue to receive treatment until 7-14 days before IMP administration. 4. Documented informed consent; willingness to adhere to protocol and required long-term follow-up as evidenced by written informed consent.
Exclusion criteria
Exclusion criteria: 1. Subjects unable or unwilling to meet requirements of the study. 2. Participation in a clinical study with an investigational drug in the 6 months prior to enrolment in this trial. 3. Subjects who are unable to perform the 6MWT. 4. History of severe anaphylactoid reaction to Naglazyme in subjects receiving ERT that could affect the safety (severe reaction is meant to be an event with respiratory impairment that is life-threatening). 5. Presence of tracheostomy or need of ventilatory assistance. 6. Subjects with evidence of progressive severe myelomalacia that is predicted to require neck surgery in the first six months after enrolment. 7. Serum AST or ALT above the upper limit of normal range at the baseline evaluations (Baseline 2, -5 days). 8. Co-existence of chronic diseases or clinically relevant abnormal baseline laboratory values; infections with hepatitis B, C, or HIV (Baseline 1). 9. Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs within 2 weeks prior to IMP administration. 10. Female individuals of childbearing age who are pregnant or nursing or unwilling to use effective contraception for at least one year post-IMP administration. 11. Fertile male individuals who are unwilling to use male barrier contraceptives such as condom. 12. Any other condition that would not allow the subject to complete follow-up examinations during the course of the study and that, in the opinion of the Investigator, would make the subject unsuitable for the study. 13. Detectable serum neutralizing antibodies (NAB) against AAV8 vector (Screening) 14. Presence of serum antibodies anti-ARSB above the limit of detection of the assay (antibodies anti-ARSB titer >31250 or positive to the value of dilution 1:10 according to the performed assay) at Screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary safety endpoints will be based on physical examination and laboratory tests. • Overall short-term and long-term safety and tolerability measured by recording of adverse events, physical examination including vital signs, laboratory tests and liver ultrasound. • Inflammation of the liver, as shown by an elevation in transaminases. • Kidney fuction by monitoring of parameters: creatinine, albumin, total protein and BUN • Presence of immune-complexes by monitoring of C3 and C4 complement protein level The primary efficacy endpoint will be urinary GAG excretion levels. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary efficacy endpoints will include: • Leukocyte ARSB levels (enzyme activity), • Endurance measured by 6-minute walk test (6MWT) and 3-minute stair climb test (3MSCT), • Forced vital capacity (FVC) and forced expiratory volume at 1 minute (FEV1) in cooperative subjects. Tertiary efficacy endpoints will include: • Height and Weight • Health Assessment Questionnaire and Childhood Health Assessment Questionnaire (HAQ, CHAQ) scores, • Visual acuity and ocular abnormalities by full ocular examination. • Cardiac function through ECG and echocardiography to monitoring cardiac parameters Additional exploratory endpoints will include: • Urinary and serum GAG levels by more sensitive assays that are under investigation. • ARSB protein level • Anti-AAV Antibodies | — |
Countries
Italy, Netherlands, Turkey
Outcome results
None listed