E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The clinical trial will be conducted on patients with Mucopolysaccharidosis Type VI. MPS VI is characterized by growth retardation, corneal clouding, cardiac valve disease, organomegaly, skeletal dysplasia, without central nervous system involvement |
La Sperimentazione verrà eseguita su pazienti affetti da Mucopolissacaridosi di tipo VI. La patologia è caratterizzata da ritardo nella crescita, opacità corneale, patologie relative alla valvola cardiaca, organomegalia, displasia scheletrica, senza il coinvolgimento del sistema nervoso centrale. |
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E.1.1.1 | Medical condition in easily understood language |
Mucopolysaccharidosis type VI,Lysosomal Storage Disorder |
Mucopolisaccaridosi di tipo VI, malattia da accumulo lisosomiale |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059318 |
E.1.2 | Term | Hepatic cancer stage I |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10054889 |
E.1.2 | Term | Transaminases increased |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037933 |
E.1.2 | Term | Reaction anaphylactic anaphylactoid |
E.1.2 | System Organ Class | 100000004870 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019717 |
E.1.2 | Term | Hepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary 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 evaluate the safety of the three different doses of drug 2x10^11 gc/kg , 6x10^11 gc/kg , 2x10^12 gc/kg |
valutare la sicurezza di tre differenti dosi di farmaco 2x10^11 gc/kg , 6x10^11 gc/kg , 2x10^12 gc/kg |
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E.2.2 | Secondary objectives of the trial |
to investigate the efficacy of the drug |
valutare l'efficacia del farmaco |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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1.I soggetti devono avere una diagnosi clinica, biochimica e molecolare di MPS VI.
2.I soggetti dovranno avere un’età superiore ai 4 anni.
3.I soggetti dovranno riceve la Terapia Enzimatica Sostitutiva (ERT) per almeno 12 mesi prima dell’arruolamento e dovranno continuare a ricevere il trattamento fino a 7-14 giorni prima della somministrazione del farmaco sperimentale.
4.Consenso informato firmato. Volontà ad aderire al protocollo e ad un follow-up a lungo termine.
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E.4 | Principal exclusion criteria |
1.Subjects unable or unwilling to meet requirements of the study.
2.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).
3.Serum AST or ALT above the upper limit of normal range at the baseline evaluations (Baseline 2, -5 days).
4. Detectable serum neutralizing antibodies (NAB) against AAV8 vector.
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1.I soggetti che non sono in grado o che non vogliono soddisfare le esigenze dello studio. 2.La prova di una reazione anafilattica grave al Naglazyme nei soggetti trattati con ERT che potrebbe incidere sulla sicurezza (grave reazione anafilattica potrebbe tradursi anche in un evento con insufficienza respiratoria) 3.Livelli sierici di ALT e AST al di sopra del limite massino di normalità durante le valutazioni della Baseline (3-5 giorni) 4.La presenza nel siero di anticorpi neutralizzanti (NAB) contro il vettore AVV8.
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E.5 End points |
E.5.1 | Primary end point(s) |
•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.
•Urinary GAG excretion levels
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•Sicurezza generale a breve e lungo termine e tollerabilità misurata dalla registrazione di eventi avversi, esami fisici inclusi i parametri vitali , esami di laboratorio ed ecografia epatica
•Infiammazioni epatiche determinate in base ad un aumento di transaminasi.
•Livelli di GAG urinari
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The safety endpoints will be monitored in the days immediately following the infusion of the drug (short-term monitoring) and during the following weeks, months and years (monitoring long-term). L 'outcome of efficacy will be evaluated during the three days post treatment and at 4 and 9 months, a year, a year and a half, two years, two and a half years and three years. |
Gli end point di sicurezza saranno monitorati nei giorni immediatamente successivi l'infusione del farmaco (monitoraggio paramentri di sicurezza a breve termine) e durante le settimane, i mesi e gli anni successivi (monitoraggio paramentri di sicurezza a lungo termine). L' end point di efficacia verrà valutato nei tre giorni èpst trattamento e a 4 e 9 mesi, un anno, un anno e mezzo, due anni, due anni e mezzo e tre anni. |
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E.5.2 | Secondary end point(s) |
•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.
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•Livelli di ARSB nei leucociti (attività enzimatica), •Livelli di durata in termini di resistenza misurati attraverso il 6-minute walking test (6MWT) e il 3-minute stairs climbing test (3MSCT), •Capacità vitale forzata (FVC) e del volume espiratorio in 1 minuto (FEV1) in soggetti cooperanti.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Leukocyte ARSB levels (enzyme activity) measured at screening; the day before treatment: 3 weeks post-treatment; 10 weeks post-treatment; 14 weeks post-treatment ; 4,9,12 months post-trattamento1.5, 2, 2.5, 3 years post-treatment •Endurance measured by 6-minute walk test (6MWT) and 3-minute stair climb test (3MSCT) measured at baseline1; 2 days pre-treatment; 4,9,12 months post-treatment; 1.5, 2, 2.5, 3 years post-trattamento, •Forced vital capacity (FVC) and forced expiratory volume at 1 minute (FEV1) in cooperative subjects measured at baseline1; 1 o 2 days pre-treatment; 4,9,12 months post-treatment; 1.5, 2, 2.5, 3 years post-treatment
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•Livelli di ARSB nei leucociti (attività enzimatica) misurata allo screening; il giorno prima del trattamento; 3 settimana post-trattamento; 10 settimane post-trattamento; 14 settimane post-trattamento; 4,9,12 mesi post-trattamento; 1.5, 2, 2.5, 3 anni post-trattamento •Livelli di durata in termini di resistenza misurati attraverso il 6-minute walking test (6MWT) e il 3-minute stairs climbing test (3MSCT) valutati alla baseline1; 2 giorni pre-trattamento; 4,9,12 mesi post-trattamento; 1.5, 2, 2.5, 3 anni post-trattamento •Capacità vitale forzata (FVC) e del volume espiratorio in 1 minuto (FEV1) in soggetti cooperanti misurati alla baseline1; 1 o 2 giorni pre-trattamento; 4,9,12 mesi post-trattamento; 1.5, 2, 2.5, 3 anni post-trattamento
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |