E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subject has a genetically confirmed diagnosis of any of the following urea cycle disorders: ASS, CPS1, ASL, OTC Subjects without UCD can have other stable illness that not interfere with the clinical trial according to the investigator judgement (subjects without UCD will not be enrolled in Germany) |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10080020 |
E.1.2 | Term | Urea cycle disorder |
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 assess the intra-subject inter-occasion variability of ureagenesis in pediatric subjects with a confirmed diagnosis of neonatal-onset UCD over a period of up to 36 weeks using a 15NH4Cl diagnostic tracer. |
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E.2.2 | Secondary objectives of the trial |
Key Sec Obj:•To assess the intra-subject inter-occasion variability of ureagenesis in pediatric subjects with a confirmed diagnosis of infantile-onset UCD over a period of up to 36 weeks using a 15NH4Cl diagnostic tracer.•To assess disease stability in pediatric subjects with a confirmed diagnosis of UCD over a period of up to 36 weeks. Secondary Objcs:•To assess the ureagenesis and its variability in pediatric subjects without UCD over a period of 12 weeks using a 15NH4Cl diagnostic tracer. •To compare the inter-subject variability and extent of impairment of ureagenesis in subjects with UCD with the ureagenesis capacity in pediatric subjects without UCD using a 15NH4Cl diagnostic tracer. •To correlate the ureagenesis, in both subjects with and without UCD, as determined by the 15NH4Cl tracer assay, with blood levels of ammonia, citrulline and glutamine. Safety Objectives: To assess the safety and tolerability of 15NH4Cl diagnostic tracer in pediatric subjects with and without UCD.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject must meet ALL of the following criteria at Screening to be eligible for this trial, with the exception of criteria 1 and 2 which do not apply to subjects without UCD and criterium 3 that only applies for subjects without UCD (subjects without UCD will not be enrolled in Germany): Only for subjects with UCD 1. Subject has a genetically confirmed diagnosis of any of the following urea cycle disorders: ASS, CPS1, ASL, OTC. Note: All subjects should have genotyping information available, however if an exact genetic diagnosis is not available, diagnosis of the UCD sub-type may be confirmed by well accepted biochemical parameters 2. Subject has neonatal or infantile onset of UCD signs and symptoms within the first 12 months of life; or subjects who have a family history of UCD and are asymptomatic after birth due to a therapeutic regimen started directly after birth; Only for subjects without UCD 3. Subjects without UCD can have other stable illness that does not interfere with the clinical trial according to the investigator judgement; For all subjects (with and without UCD) 4. Male and female subjects aged up to 10 years, inclusive; 5. Subject has a body weight within the 5-95th percentile of the corresponding age according to the CDC Growth Charts; 6. Subject has stable clinical conditions (any acute condition needs to be stabilised/treated before inclusion); 7. The parent(s) / legal representative(s) agrees that the subject will not participate in any interventional clinical trial with an investigational drug for the duration of the trial until the final follow-up visit; 8. Ability and willingness of the parent(s) / legal representative(s) to comply with the protocol requirements, including ability to bring the subject to the scheduled trial visits; 9. Written informed consent by the parent(s) / legal representative(s) of the subject, and assent from the pediatric subject when required by local regulations, the IRB/IEC or trial site.
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E.4 | Principal exclusion criteria |
A subject must meet NONE of the following criteria at Screening to be eligible for this trial, with the exception of criterion 1 which does not apply to subjects without UCD (subjects without UCD will not be enrolled in Germany): Only for subjects with UCD 1. Subject has any suspected UCD of any sub-type. Note: subjects suspected of having a UCD of any sub-type, but without either confirmatory genotyping information or a typical biochemical diagnostic pattern for any UCD gene defect, will not be enrolled in this trial. For all subjects (with and without UCD) 2. Subject is a premature neonate (up to 37 gestation weeks not completed); 3. Subject is in a period of significant post-natal weight drop based on the judgement of the investigator ; 4. Subject has received any investigational compound within 30 days (or 5 half-lives, whichever is longer) prior to first dose of diagnostic tracer and according to the investigator judgement could interfere with the clinical trial; 5. Subject has any other acute severe / other genetic / life limiting disorder that would interfere with ethical and/or medical standards in the conduct or follow up of the trial. 6. Subject has acute liver failure, clinical or radiological evidence of liver fibrosis or cirrhosis, or presents a hepatic or extrahepatic malignancy. 7. Subject has abnormal renal function, or an estimated glomerular filtration rate (eGFR) of below 40 mL/min/1.73 m2 (aged up to 2 years) or below 60 mL/min/1.73 m2 (aged 2 to 10 years), as calculated by the pediatric Schwartz equation. This assessment may be repeated once to exclude spurious values. 8. Subject has a supine or semi-supine systolic blood pressure below 60 mm Hg, or a supine or semi-supine heart rate (HR) outside the range of 90-180 bpm (aged up to 28 days), or 110-160 bpm (aged 1 to 12 months), 100-150 bpm (aged 1 to 5 years) or 80-120 bpm (aged 5 to 10 years), confirmed on repeat testing (WHO Pocket Book of Hospital Care for Children 2013, Samuels 2010). 9. Subject has abnormal electrocardiogram (ECG) values as follows, based on the mean of the triplicate ECG values, and confirmed on repeat triplicate testing (Lambrechts and Fourie 2020): o PR interval above 120 msec (aged up to 28 days), or 140 msec (aged 1 to 12 months), 170 msec (aged 1 to 5 years) or 190 msec (aged 5 to 10 years); o QRS interval above 70 msec (aged up to 28 days), or 75 msec for infants (aged 1 to 12 months), 110 msec (aged 1 to 5 years) or 120 msec (aged 5 to 10 years); o QT interval corrected for HR using Fridericia’s formula (QTcF) above 420 msec for neonates (aged up to 28 days) or 440 msec for infants (aged 1 to 10 years); 10. Subject has haemoglobin levels outside the pediatric-specific normal range of the local laboratory. The test may be repeated once to exclude spurious values. 11. Subject has any clinical or laboratory abnormality of Grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) v5, except Grade 3 elevations in ammonia, alanine aminotransferase (ALT), aspartate aminotransferase (AST) or gamma glutamyl transpeptidase (GGT) in a clinically stable subject. The test(s) may be repeated once to exclude spurious values. 12. Subject has any other clinically significant abnormal physical examination, vital signs, ECG or laboratory finding that, according to the judgement of the investigator, may put the subject at increased risk by participating in this study
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E.5 End points |
E.5.1 | Primary end point(s) |
•The intra-subject inter-occasion variability of the [15N] urea enrichment area under the plasma concentration-time curve over 2 hours (AUC0-2) following up to 4 15NH4Cl diagnostic tracer administrations over a 36-week period to pediatric subjects with neonatal-onset UCD. |
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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) |
Key Secondary Endpoints: •The intra-subject inter-occasion variability of the [15N] urea enrichment area under the plasma concentration-time curve over 2 hours (AUC0-2) following up to 4 15NH4Cl diagnostic tracer administrations over a 36-week period to pediatric subjects with infantile-onset UCD. •The number of pediatric subjects with UCD demonstrating stable disease at Weeks 0, 12, 24 and 36. •The blood concentrations of ammonia, glutamine and citrulline up to 2 hours following o up to 4 15NH4Cl diagnostic tracer administrations to pediatric subjects with UCD (Weeks 0, 12, 24 and 36). o up to 2 15NH4Cl diagnostic tracer administrations to pediatric subjects without UCD (Weeks 0 and 12). •The number of hyperammonaemia events and crises experienced since the previous trial visit at Weeks 12, 24 and 36 (subjects with UCD only). •The number of pediatric subjects following a stable protein diet, with no unplanned adjustments since the previous trial visit, at Weeks 12, 24 and 36 (subjects with UCD only). Secondary Endpoints: •The intra-subject inter-occasion variability of the [15N] urea enrichment area under the plasma concentration-time curve over 2 hours (AUC0-2) following o up to 4 15NH4Cl diagnostic tracer administrations over a 36-week period to pediatric subjects with infantile-onset UCD. o up to 2 15NH4Cl diagnostic tracer administrations over a 12-week period to pediatric subjects without UCD. •The inter-subject variance of the [15N] urea enrichment area under the plasma concentration-time curve over 2 hours (AUC0-2) following each 15NH4Cl diagnostic tracer administration o to pediatric subjects with neonatal-onset UCD (Weeks 0, 12, 24 and 36). o to pediatric subjects with infantile-onset UCD (Weeks 0, 12, 24 and 36). o to pediatric subjects without UCD (Weeks 0 and 12). •The inter-subject inter-occasion variability of the [15N] urea enrichment area under the plasma concentration-time curve over 2 hours (AUC0-2) following o up to 4 15NH4Cl diagnostic tracer administrations over a 36-week period to pediatric subjects with neonatal-onset UCD. o up to 4 15NH4Cl diagnostic tracer administrations over a 36-week period to pediatric subjects with infantile-onset UCD. o up to 2 15NH4Cl diagnostic tracer administrations over a 12-week period to pediatric subjects without UCD. •The inter-subject variance of the area under the blood concentration-time curve over 2 hours (AUC0-2) for ammonia, citrulline and glutamine following o up to 4 15NH4Cl diagnostic tracer administrations over a 36-week period to pediatric subjects with UCD. o up to 2 15NH4Cl diagnostic tracer administrations over a 12-week period to pediatric subjects without UCD. Safety Endpoints: •Adverse events (AEs); physical, neurological and child development examination findings; vital signs; ECG, clinical laboratory tests; biochemical parameters; plasma amino acid levels; frequency and severity of hyperammonaemia events and crises; and compliance to protein intake and concomitant medication.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
According to the protocol |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Ureagenesis assessment using 15N labelled ammonium chloride (15NH4Cl) |
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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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Subjects without diagnosis of UCD will not be enrolled in Germany |
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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
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E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 | No |
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 |
Israel |
Saudi Arabia |
Austria |
France |
Spain |
Switzerland |
Germany |
Italy |
Belgium |
Turkey |
United Kingdom |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |