E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neonatal-onset type of the following urea cycle disorders
(UCD):
ornithine transcarbamylase deficiency (OTCD),
carbamoylphosphate synthetase I deficiency (CPS1D), or
argininosuccinate synthetase deficiency (ASSD or
citrullinemia) |
|
E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
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 investigate the safety and efficacy of multiple HHLivC infusions in children with ornithine
transcarbamylase deficiency (OTCD), carbamoylphosphate synthetase I deficiency (CPS1D), or
argininosuccinate synthetase deficiency (ASSD or citrullinemia).
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E.2.2 | Secondary objectives of the trial |
To investigate the safety and efficacy of multiple HHLivC infusions in children with OTCD, CPS1D, or
ASSD as determined by the assessments noted within the secondary variables.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject could have been included in the study if all of the following criteria were met:
1. Males or females whose gestational corrected age (calculated from term delivery or 37 weeks of
gestation) on the day of enrollment is 1 day up to 5 years of age.
2. Complete OTCD, CPS1D, or ASSD with neonatal-onset type (OTCD, CPS1D: clinical presentation
with plasma ammonia > 500 μmol/L within the first week of life; ASSD: clinical presentation with
plasma ammonia > 500 μmol/L within the first 4 weeks of life) or prospectively diagnosed relative of
a subject with the same confirmed diagnosis of complete OTCD/CPS1D/ASSD. Early information
about the disease (eg by prenatal diagnosis or newborn-screening) may enable early treatment, which
can prevent rising of ammonia to levels >500 μmol/L despite neonatal onset type (complete
deficiency). However, in such cases a subject may be eligible after thorough check of the data
available (eg DNA analysis) by the investigator.
Further biochemical parameters and DNA analyses confirmed diagnosis prior to or after inclusion in
the protocol according to the following diagnostic criteria:
OTCD Identification of pathogenic mutation and/or
Pedigree analysis and/or
<20% of control OTC activity in liver and/or
Elevated urinary orotate (>20 uM/mM) after allopurinol challenge test
CPS1D Decreased (<20% of control) CPS-1 enzyme activity in liver and/or
Identified pathogenic mutation*
ASSD >10 fold elevation of citrulline in plasma and/or
Decreased ASS enzyme activity in cultured skin fibroblasts or other
appropriate tissue and/or
Identified pathogenic mutation
*A mutation analysis to exclude N-acetylglutamate synthetase deficiency (NAGSD) is required to differentiate
from a suspected CPS1D diagnosis. Deoxyribonucleic acid (DNA) analysis for pathogenic mutation of CPS-1 is
planned after enrollment.
3. Plasma ammonia level ≤250 μmol/L at time of enrollment.
4. Written informed consent obtained from the subject’s legal representatives. |
|
E.4 | Principal exclusion criteria |
A subject was not included in the study if any one of the following criteria were met:
1. Weight ≤3.5 kg.
2. Presence of acute infection at the time of inclusion.
3. Severe chronic or systemic disease other than study indication.
4. Structural liver disease (eg, cirrhosis, portal hypertension) or venoocclusive diseases.
5. Portal vein thrombosis.
6. Known diagnosis of hereditary thrombophilia (eg, factor V Leiden, prothrombin 20210A variant) or
parental history of hereditary thrombophilia and absence of thrombophilia testing in subject.
7. Prothrombin time (PT) or partial thromboplastin time (PTT) (or activated partial thromboplastin time
[aPTT]) of >1.5 times the upper limit of normal OR platelet count < 50,000 mm3.
8. Contraindications for immunosuppression.
9. Live vaccination planned during the study.
10. Live vaccination within 4 weeks prior to beginning study.
11. Required valproate therapy.
12. Participation in other clinical trials, or received experimental medication within the last 30 days.
Note: An individual who was initially excluded from study participation based on ≥1 of the above timelimited
criteria (eg, acute infection) could have been reconsidered for enrollment once the condition was
resolved contingent on the subject continuing to meet all other entry criteria. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change in 13C urea formation from Baseline to 2 and 4 months (or earlier, if orthotopic liver transplant [OLT]
is performed prior to V19) after first HHLivC infusion. The plasma concentration of 13C urea at any timepoint
was measured. The following parameters were presented at Baseline and after HHLivC therapy (per visit) and
per individual subject:
the peak level of 13C urea concentration in plasma [Cmax]
the time when the peak level of 13C urea concentration in plasma is reached [Tmax]
Area under the curve (AUC [0-120min]) and AUC (0-latest time point) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Number, duration and severity of metabolic crises (maximum ammonia concentration, duration of
coma)
Growth and nutritional status
Use of ammonia scavenging drugs
If an OLT was received, increase in the respective enzyme activity in samples from the explanted
liver taken after OLT compared with the enzyme activity in the liver biopsy taken prior to the first
HHLivC infusion (only OTCD and CPS1D).
If an OLT was received, detection of donor cell material in samples from the explanted liver taken
after OLT was investigated and samples were compared with the liver biopsy taken prior to the
HHLivC infusion.
Laboratory parameters: plasma ammonia, glutamine, urea, and in OTCD: urine orotic acid
concentration
Survival at 6 months after first HHLivC infusion |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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) | No |
E.7.1.1 | First administration to humans | No |
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) | Yes |
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 | Yes |
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.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA 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.8.9.2 | In all countries concerned by the trial years | 6 |
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 |