E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
neonatal hyperammonemic encephalopathy associated with inborn liver metabolic diseases |
iperammoniemia e encefalopatia in neonati con malattie metaboliche congenite del fegato |
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E.1.1.1 | Medical condition in easily understood language |
inborn metabolic hepatic diseases |
malattie metaboliche congenite del fegato |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059521 |
E.1.2 | Term | Methylmalonic aciduria |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058299 |
E.1.2 | Term | Argininosuccinate lyase deficiency |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052450 |
E.1.2 | Term | Ornithine transcarbamoylase deficiency |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058297 |
E.1.2 | Term | Carbamoyl phosphate synthetase deficiency |
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 evaluate hepatic and extra-hepatic complications after liver intraparenchymal HLSC injection in neonates suffering from inborn liver metabolic diseases causing life-threatening neonatal-onset of hyperammonemic encephalopathy |
valutare le complicanze epatiche ed extra-epatiche a seguito della somministrazione intraparenchimale delle HLSCs in neonati con iperammonemia e encefalopatia dovute a malattie metaboliche genetiche |
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E.2.2 | Secondary objectives of the trial |
To evaluate plasma ammonia levels (< 100 µmol/l) following the treatment; To evaluate the daily protein intake maintaining plasma ammonia levels < 100 µmol/l (measure: quantification of daily protein tolerance increase (g/kg/day) following the treatment); To reduce clinically significant hyperammonemic episodes (measure: number of hyperammonemic episodes following the treatment); To defer the time of liver transplantation from the scheduled time (measure: difference in months between the age at liver transplantation following the treatment and the age previously scheduled) |
Valutare i livelli di ammonemia (< 100 µmol/l) dopo il trattamento; Valutare l’assunzione giornaliera di proteine mantenendo livelli di ammoniemia < 100 µmol/l (misurare: quantificare la toleranza giornaliera di proteine (g/kg/giorno) dopo il trattamento); Ridurre gli episodi clinicamente rilevanti di iperammoniemia (misurare: il numero di episodi di iperammoniemia dopo il trattamento); Valutare la possibilità di posticipare il trapianto di fegato (misurare: la differenza in mesi tra l’età del neonato al momento del trapianto dopo trattamento e quella al trapianto determinato precedentemente)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
neonatal-onset hyperammonemic encephalopathy; formal biochemical diagnosis of one of the five inborn metabolic diseases, as listed in the Table 1; formal evaluation for early liver transplantation; being referred to the Presidio Ospedaliero Infantile Regina Margherita, Centro delle Malattie Metaboliche, Torino, Italy;
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encefalopatia iperammoniemica neonatale; diagnosi con una conferma biochimica di uno dei 5 deficit elencati in Tabella 1; valutazione formale di idoneità al trapianto di fegato; essere ricoverati presso il Presidio Ospedaliero Infantile Regina Margherita, Centro delle Malattie Metaboliche, Torino, Italia
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E.4 | Principal exclusion criteria |
Refusal of signing the specific informed consent for entering the study; Evidence of uncontrolled coagulopathy;
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rifiuto dei genitori/tutori di firmare il modulo per il consenso informato; evidenza di coagulopatia incontrollabile
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety endpoints: Hepatic complications: portal vein thrombosis, intrahepatic hematoma, injury of the hepatic artery, arterio-portal, portal-biliary and arterio-biliary fistula, acute hepatic cytolysis > 20 times normal, clinical and biochemical signs of liver failure (ascites, development of jaundice with conjugated bilirubin above 3 mg/dL, alterations in INR > 2.5), appearance of cancer-like liver nodular lesions. Extra-hepatic complications: pulmonary embolism, significant extra-hepatic (abdominal and/or chest) haemorrhage (requiring blood transfusion and / or specific treatment), documented sepsis with bacteremia, adverse reactions to sedative drugs administered for interventional radiological procedure.
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Endpoints di sicurezza: Complicanze epatiche: trombosi della vena portale, ematoma intraepatico, lesione dell'arteria epatica, fistola arterio-portale, porta-biliare o arero-biliare, citolisi acuta epatica, evidenze cliniche e di laboratorio di insufficienza epatica (ascite, sviluppo di itterizia in associazione a bilirubina superiore a 3 mg/dL, alterazioni dell’INR > 2.5), comparsa di lesioni nodulari epatiche, simil-tumorali. Complicanze extra-epatiche: embolia polmonare, emorragia extra-epatica toracica e/o addominale di entità significativa (con necessità di trasfusione e/o trattamento specifico), sepsi accompagnata da batteriemia, reazioni avverse a sedativi somministrati nel corso della procedura di radiologia interventistica
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated daily by monitoring adverse events, in the 15 days following the treatment. Other safety parameters will be evaluated weekly. A Safety Follow-up visit is planned, 4 weeks after last dose administration. |
l'endpoint primario sarà valutato giornalmente mediante accertamento degli eventi avversi, nei 15 giorni successivi al trattamento. Altri parametri di sicurezza saranno valutati settimanalmente. E' prevista una visita di Safety Follow-up 4 settimane dopo la somministrazione dell'ultima dose. |
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E.5.2 | Secondary end point(s) |
to evaluate plasma ammonia levels (< 100 µmol/l following the treatment); to evaluate the daily protein intake, maintaining plasma ammonia levels < 100 µmol/l (measure: quantification of daily protein tolerance increase (g/kg/day) following the treatment); to reduce clinically significant hyperammonemic episodes (measure: number of hyperammonemic episodes following the treatment); to defer the time of liver transplantation from the scheduled time (measure: difference in months between the age at liver transplantation following the treatment and the age previously scheduled) |
Valutare i livelli di ammonio nel plama (< 100 µmol/l) dopo il trattamento; Valutare l’assunzione giornaliera di proteine, mantenendo livelli di ammonio nel plama inferiori a 100 µmol/l (quantificare l’aumento di tolleranza giornaliera di proteine (g/kg/giorno) dopo il trattamento); Ridurre in maniera significativa gli episodi clinicamente rilevanti di iperammoniemia (misurare: il numero di episodi di iperammoniemia dopo il trattamento); Valutare la possibilità di posticipare il trapianto di fegato (misurare: la differenza in mesi tra l’età del neonato al momento del trapianto dopo trattamento e quella al trapianto determinato precedentemente)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be evaluated weekly and at the Safety Follow-up visit, 4 weeks after administration of last dose |
gli endpoints secondari saranno valutati settimanalmente e nella visita di Safety Follow-up prevista 4 settimane dopo la somministrazione dell'ultima dose |
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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 | No |
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.8.5 | The trial involves multiple Member States | No |
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 | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |