Urease Inhibitor Drug Treatment for Urea Cycle Disorders

• Register: ClinicalTrials.gov
• Last refreshed on: 5 September 2016
• Main ID: NCT02670889
• Date of registration: 14/01/2016
• Prospective Registration: Yes
• Primary sponsor: Nicholas Ah Mew
• Public title: Urease Inhibitor Drug Treatment for Urea Cycle Disorders
• Scientific title: Manipulating the Gut Microbiome in Urea Cycle Disorders
• Date of first enrolment: November 2016
• Target sample size: 16
• Recruitment status: Not yet recruiting
• URL: https://clinicaltrials.gov/show/NCT02670889
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 1/Phase 2

Contacts

• Name: Nicholas Ah Mew, MD

• Name: Marshall L Summar, MD
• Affiliation: Children's National Health System

• Name: Nicholas Ah Mew, MD
• Affiliation: Children's National Health System

Key inclusion & exclusion criteria

For Healthy Adult Volunteers:

Inclusion Criteria:

- Compliant with receiving medications orally and intravenously

- Compliant with providing blood and urine samples

For Urea Cycle Disorder Adults:

Inclusion Criteria:

- Compliant with receiving medications orally and intravenously

- Compliant with providing blood and urine samples

- Established diagnosis of CPSD, OTCD, ASSD or ASLD as follows:

- Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control)
CPS I enzyme activity in liver or an identified pathogenic mutation

- Diagnosis of OTC deficiency, defined as the identification of a pathogenic
mutation, linkage analysis in an affected family, less than 20% of control of
OTC activity in the liver, or elevated urinary orotate (greater than 20 uM/mM)
in a random sample or following allopurinol loading with absence of
argininosuccinic acid

- Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal
to 10-fold elevation of citrulline in plasma, decreased AS enzyme activity in
cultured skin fibroblasts or other appropriate tissue, or identification of a
pathogenic mutation in the AS gene

- Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the
presence of argininosuccinic acid in the blood or urine, decreased AL enzyme
activity in cultured skin fibroblasts or other appropriate tissue, or
identification of a pathogenic mutation in the AL gene

Exclusion Criteria (both arms):

- Current or prior Helicobacter pylori infection

- Chronic gastrointestinal illness (e.g., inflammatory bowel disease)

- Chronic renal failure

- Taking probiotic medications within a week of study start date

- Currently pregnant or lactating. Documentation of a negative pregnancy test within a
week prior to testing is required, unless pre-menarchal or menopausal, experiencing
menses that week, or other circumstances which preclude pregnancy (e.g.
hysterectomy).

- Presence of acute infection at the time of inclusion

- Participation in any other clinical interventional trial or received experimental
medication within the last 30 days

- Any clinical or laboratory abnormality or medical condition that, at the discretion
of the investigator, may put the subject at an additional risk by participating in
this study



Age minimum: 18 Years
Age maximum: 60 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Argininosuccinate Synthetase Deficiency (Citrullinemia)

Argininosuccinic Acid Lyase Deficiency (Argininosuccinic Aciduria)

Carbamyl-Phosphate Synthase I Deficiency

Ornithine Transcarbamylase Deficiency

Intervention(s)

Drug: Isotopic Intravenous [13C]-Urea

Drug: Acetohydroxamic Acid

Primary Outcome(s)

Blood and urine measurements of isotopic [13C]-urea concentration [Time Frame: Blood: 0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4; Urine: 0, 240 minutes on Day 1 and Day 4]

Blood measurements of isotopic [13-CO2] concentration [Time Frame: 0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4]

Secondary Outcome(s)

Blood plasma samples measuring glutamine concentration [Time Frame: 0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4]

Blood and urine samples measuring urea concentration [Time Frame: Blood: 0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4; Urine: 0, 240 minutes on Day 1 and Day 4]

Blood samples measuring ammonia concentration [Time Frame: 0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4]

Secondary ID(s)

CNMC 7230, U54-HD061221

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Children's Hospital of Philadelphia

Data Management and Coordinating Center (DMCC)