Clinical trial NCT01549015: Study in Healthy Subjects, Patients With Urea Cycle Disorders (UCD) and Carriers of UCD Mutations to Evaluate Urea Cycle Function
Official title: Open, Prospective, Diagnostic, Multicentre Study in Healthy Subjects, Patients With Urea Cycle Disorders (UCD), and Carriers of UCD Mutations, to Evaluate in Vivo Ureagenesis Measured After a Single Application of Sodium [1,2-13C]-Acetate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Urea Cycle Disorders
Keywords: Urea Cycle Defects
CPSD
OTCD
ASSD
ASLD
Lead sponsor: Cytonet GmbH & Co. KG
Sponsor class: INDUSTRY
Collaborators: name: CRS Clinical Research Services Mannheim GmbH
First posted: 2012-03-08
Enrollment: 37
Sex: ALL
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: This diagnostic study will be performed to investigate the performance of the urea cycle in healthy subjects, asymptomatic carriers of Urea Cycle Disorders (UCD) mutations and subjects with genetically proven urea cycle disorders. The ureagenesis rate will be measured by 13C incorporation assay, a method for in vivo measurement of urea cycle performance with stable isotopes.

Detailed description: In this diagnostic study CCD09, the urea metabolism in UCD subjects (patients and carriers) and healthy subjects of different age and sex will be assessed by measurement of the incorporation of 13C from orally taken sodium \[1,2-13C\]-acetate into urea by 13C stable isotope ratio detection. The aim of the study is to determine the 13C urea production and to quantify the total urea production in healthy subject, gene defect carrier or patient as marker for the functioning of the urea cycle. Since there are still only few data available using this specific method for measurement of urea cycle performance, the aim of this study CCD09 is to gain additional results on the 13C assay. To this end, comparison will be made between 13C urea production observed in healthy subjects, UCD patients, and asymptomatic mutation carriers.

An evaluation of this study may also enable the treating physician to better judge the severity of disease and the future risk of metabolic decompensations in patients as well as the potential risk for so far asymptomatic carriers.

Eligibility criteria: Inclusion Criteria:

All study groups:

• Written informed consent given by subjects or his/her parents/legal guardians who are able to understand and follow instructions related to the study

Group 1 Healthy Volunteers:

* Age: 18 - 65 years
* Healthy subjects
* No clinical or laboratory parameter outside normal ranges at screening and judged as clinically relevant by the investigator

Group 2 Symptomatic UCD patients with genetically confirmed CPSD, OTCD, ASSD, or ASLD:

Age: 0 - 65 years

* Symptomatic subjects with genetically confirmed Carbamylphosphate synthetase I Deficiency \[CPSD\], Ornithine Transcarbamylase Deficiency \[OTCD\], Argininosuccinate Synthetase Deficiency \[Citrullinaemia type I\], Argininosuccinate Lyase Deficiency \[ASLD\]
* at least 1 metabolic decompensation with clinical signs of hyperammonemia in medical history or genetically confirmed and prospectively treated siblings of symptomatic patients, even without clinical symptoms
* Confirmed diagnosis and medical history available (in particular number and severity of metabolic crises)

Group 3 Asymptomatic carriers of UCD mutations:

* Age: 0 - 65 years
* Asymptomatic carriers of mutations for Carbamylphosphate synthetase I Deficiency \[CPSD\], Ornithine Transcarbamylase Deficiency \[OTCD\], Argininosuccinate Synthetase Deficiency \[Citrullinaemia type 1\], Argininosuccinate Lyase Deficiency \[ASLD\] no dietary protein restriction, no intake of ammonia scavenging drugs, no known metabolic decompensation with clinical signs of hyperammonemia

Group 4:

* Infants between 8 - 10 kg body weight Symptomatic subjects with genetically confirmed Carbamylphosphate synthetase I Deficiency \[CPSD\] Ornithine Transcarbamylase Deficiency \[OTCD\] Argininosuccinate Synthetase Deficiency \[Citrullinaemia type I\] Argininosuccinate Lyase Deficiency \[ASLD\] at least 1 metabolic decompensation with clinical signs of hyperammonemia in medical history or genetically confirmed and prospectively treated siblings of symptomatic patients, even without clinical symptoms
* Confirmed diagnosis and medical history available (in particular number and severity of metabolic crises

Exclusion Criteria:

* Acute illness, including vomiting, fever or other sign of infection
* Participation in other invasive clinical trials within 30 days prior to inclusion
* Liver or renal disease
* Acute seizures
* Coma
* Bleeding disorder
* Blood ammonia \> 100 µmol/l for patients with a urea cycle disorder and blood ammonia \> normal for healthy probands and asymptomatic carriers
* Metabolic acidosis
* Pregnancy or lactation
* Body weight \< 8kg
* Chronic somatic or psychiatric disease not related to UCD

Primary outcomes:
measure: Formation of 13C-urea in plasma
timeFrame: 0 - 240 Minutes
Secondary outcomes:
measure: Vital signs
timeFrame: 0-240 min
measure: Complete blood count without differential
timeFrame: at enrollement
measure: Adverse events
timeFrame: 0-240 mins
measure: Ammonia, Amino acids, Urea in serum
timeFrame: 0-240 min
measure: CRP
timeFrame: at enrollment
measure: Venous lactate and blood gases: pH, pCO2, pO2, bicarbonate
timeFrame: at enrollment
measure: Blood glucose
timeFrame: 0 - 240 min
measure: pH and bicarbonate
timeFrame: 20 and 60 mins after administration
Other outcomes:
Locations:
city: CRS Clinical Research Services GmbH (Phase I Unit)
country: Germany
state: Mönchengladbach
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Kinderheilkunde
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg Klinik für Kinderheilkunde I
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Zentrum für Kinder- und Jugendmedizin
Study officials:
affiliation: Universitätsklinikum Heidelberg Klinik für Kinderheilkunde I
name: Georg F Hoffmann, Prof Dr med
role: PRINCIPAL_INVESTIGATOR
References: