A Phase I/II Open Label, Dose Escalation, Safety Study in Subjects with Mucopolysaccharidosis type VI (MPS VI) Using Adeno-Associated Viral Vector 8 to Deliver the human ARSB gene to Liver.
- Conditions
- enzyme impairment - Lysosomal disorder10021605
- Registration Number
- NL-OMON47624
- Lead Sponsor
- Fondazione Telethon
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Pending
- Sex
- Not specified
- Target Recruitment
- 4
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.
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.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary safety endpoints will be based on physical examination and<br /><br>laboratory tests.<br /><br>• Overall short-term and long-term safety and tolerability measured by<br /><br>recording of adverse events, physical examination including vital signs,<br /><br>laboratory tests and liver ultrasound.<br /><br>• Inflammation of the liver, as shown by an elevation in transaminases.<br /><br>• Kidney fuction by monitoring of parameters: creatinine, albumin, total<br /><br>protein and BUN<br /><br>• Presence of immune-complexes by monitoring of C3 and C4 complement protein<br /><br>level<br /><br><br /><br>The primary efficacy endpoint will be urinary GAG excretion levels.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary efficacy endpoints will include:<br /><br>• Leukocyte ARSB levels (enzyme activity),<br /><br>• Endurance measured by 6-minute walk test (6MWT) and 3-minute stair climb<br /><br>test (3MSCT),<br /><br>• Forced vital capacity (FVC) and forced expiratory volume at 1 minute (FEV1)<br /><br>in cooperative subjects.<br /><br><br /><br>Tertiary efficacy endpoints will include:<br /><br>• Height and Weight<br /><br>• Health Assessment Questionnaire and Childhood Health Assessment Questionnaire<br /><br>(HAQ, CHAQ) scores,<br /><br>• Visual acuity and ocular abnormalities by full ocular examination.<br /><br>• Cardiac function through ECG and echocardiography to monitoring cardiac<br /><br>parameters<br /><br><br /><br>Additional exploratory endpoints will include:<br /><br>• Urinary and serum GAG levels by more sensitive assays that are under<br /><br>investigation.<br /><br>• ARSB protein level<br /><br>• Anti-AAV Antibodies</p><br>