Neonates and Infants up to 3 months including with prenatally or postnatally confirmed urea cycle disorder with below listed deficiency and children aged > 3 months up to 5 years including with confirmed urea cycle disorder and unstable metabolism with deficiency of either: - Carbamyl-phosphate Synthetase I Deficiency (CPS1D) - Ornithine Transcarbamylase Deficiency (OTCD) - Argininosuccinate Synthetase Deficiency (ASSD/Citrullinaemia) can be included. MedDRA version: 18.1 Leve
Conditions
Interventions
Product Name: Human heterologous liver cells (for infusion)
Product Code: HHLivC
Pharmaceutical Form: Infusion
Sponsors
Cytonet GmbH & Co KG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Neonates and Infants up to 3 months including with prenatally or postnatally confirmed urea cycle disorder with deficiency of either: - Carbamyl-phosphate Synthetase I Deficiency (CPS1D) - Ornithine Transcarbamylase Deficiency (OTCD) - Argininosuccinate Synthetase Deficiency (ASSD/Citrullinaemia) and children aged > 3 months up to 5 years including with confirmed urea cycle disorder and unstable metabolism with deficiency of either - Carbamyl-phosphate Synthetase I Deficiency (CPSD) - Ornithine Transcarbamylase Deficiency (OTCD) - Argininosuccinate Synthetase Deficiency (Citrullinaemia) can be included. - Accessibility of the portal vein. - Plasma ammonia level =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Structural liver disease (cirrhosis, portal hypertension), or venoocclusive diseases, - Portal vein thrombosis - Body Weight less than/equal 3.5 kg - Carrier of the human immuno-deficieny virus (HIV), - Any other contraindication for immunosuppression, - Presence of acute infection at the time of inclusion, - Participation in other clinical trials or received experimental medication within last 30 days, - Live vaccination planned during the course of the study - Live vaccination within 4 weeks prior to beginning of study - Allergic disposition against contrast medium used in study and/or antibiotics used in the manufacturing process, - Required valproate therapy - Severe coagulopathy or thrombocytopenia, - Known diagnosis of hereditary thrombophilia (e.g. Factor V Leiden, Prothrombin 20210A variant) or parental history of hereditary thrombophilia and absence of thrombophilia testing in subject - Cancer, severe systemic or chronic disease other than study indication (urea cycle deficiency).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Main objective of the trial is to investigate the safety and efficacy of multiple applications of liver cell suspension in neonates, infants and children with the above defined subset of urea cycle disorders (UCD). Primary variables: • Safety of the application of liver cells as measured by oxygen saturation, portal blood pressure and flow during the infusion • Safety of the placement of an application catheter to the portal vein • Safety of the placement of an application catheter to the portal vein by evaluation of all adverse events judged to be related to the catheter placement ;Secondary Objective: Efficacy variables •Change in respective enzyme activity in explanted liver after OLT compared to enzyme activity in liver prior first cell application •Changes in 13C urea formation from baseline to 2/4 months after HHLivC infusion, and if available up to month 24 after Final Visit in case further 13C-ureagenesis tests after HHLivC infusion •Detection of donor cell material in samples from explanted liver taken after orthotopic liver transplantation compared with liver biopsy taken prior first liver cell application •Number, duration and severity of metabolic crises (maximum ammonia concentration, duration of coma) •Laboratory parameters: ammonia and amino acids in plasma and orotic acid in urine (except CPS1D) •Growth and protein intake •Nutritional status •Use of ammonia scavenging drugs •Time to death and survival 6 months after liver cell infusion Safety variables -Vital signs -Lab Parameters to monitor safety of the procedures+immunosuppression -AEs ;Primary end point(s): The primary variable is: - safety of the application of liver cells as measured by oxygen saturation, portal blood pressure and flow during the infusion - safety of the placement of an application catheter to the portal vein - safety of the placement of an application catheter to the portal vein by evaluation of all adverse events judged to be related to the catheter pla | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary safety variables: • Vital signs • Laboratory Parameters III to V to monitor the safety of the procedures and the immunosuppression • Adverse events Secondary efficacy variables: • Change in the respective enzyme activity in samples from the explanted liver taken after orthotopic liver transplantation compared to the enzyme activity in the liver biopsy taken prior to the first liver cell application • Changes in 13C urea formation from baseline to 2 and 4 months (or earlier, if OLT is performed during listing period) after first infusion of HHLivC, and if available, up to month 24 (FUV 5) after the Final Visit in case further 13C-ureagenesis tests were performed after infusion of HHLivC. • Detection of donor cell material in samples from the explanted liver taken after orthotopic liver transplantation compared with the liver biopsy taken prior to first liver cell application • Number, duration and severity of metabolic crises (maximum ammonia concentration, duration of coma) • Laboratory parameters I and II: ammonia and amino acids in plasma and orotic acid in urine (except CPS1D) • Growth and protein intake • Nutritional status • Use of ammonia scavenging drugs • Time to death and survival 6 months after liver cell infusion Exploratory variable: • Total urea and orotic acid (except CPS1D) in 12-hour urine • Urea in serum;Timepoint(s) of evaluation of this end point: Descriptive analysis: After treatment of the 5th patient an interim analysis has been conducted and did not reveal any safety concerns (conducted in July 2010). A second interim analysis was performed after the treatment of the 11th patient in Q4 2013. | — |
Countries
Germany
Outcome results
None listed