Urease Inhibitor Drug Treatment for Urea Cycle Disorders

Ornithine Transcarbamylase Deficiency Clinical Trial

Official title:

Manipulating the Gut Microbiome in Urea Cycle Disorders

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02670889
• Other study ID #: CNMC 7230, U54-HD061221
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• First received: January 14, 2016
• Last updated: August 23, 2016
• Start date: November 2016
• Est. completion date: March 2019

Study information

• Verified date: August 2016
• Source: Children's Research Institute
• Contact: Nicholas Ah Mew, MD
• Phone: 202-476-5863
• Email: NAhMew[@]childrensnational.org
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if acetohydroxamic acid (AHA) can prevent hydrolysis of urea by inhibiting the bacterial urease of gut flora of both healthy control adults as well as adults with urea cycle disorders.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 16
• Est. completion date: March 2019
• Est. primary completion date: March 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Argininosuccinate Synthetase Deficiency (Citrullinemia)
• Argininosuccinic Acid Lyase Deficiency (Argininosuccinic Aciduria)
• Argininosuccinic Aciduria
• Carbamyl-Phosphate Synthase I Deficiency
• Citrullinemia
• Ornithine Transcarbamylase Deficiency
• Urea Cycle Disorders, Inborn

Intervention

Drug:
• Acetohydroxamic Acid

• Isotopic Intravenous [13C]-Urea
Used to trace 13CO2 and 13C-urea in the blood.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Nicholas Ah Mew	Children's Hospital of Philadelphia, Data Management and Coordinating Center (DMCC)

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Abnormal Laboratory Values for Blood Hemoglobin That Are Related to Treatment	Blood samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of blood hemoglobin. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Other	Number of Participants With Abnormal Laboratory Values for White Blood Count That Are Related to Treatment	Blood samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of white blood count. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Other	Number of Participants With Abnormal Laboratory Values for Blood Platelet Count That Are Related to Treatment	Blood samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of blood platelet count. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Other	Number of Participants With Abnormal Laboratory Values for Blood AST level That Are Related to Treatment	Blood samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of blood AST levels. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Other	Number of Participants With Abnormal Laboratory Values for Blood ALT level That Are Related to Treatment	Blood samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of blood ALT levels. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Other	Number of Participants With Abnormal Laboratory Values for Blood Bilirubin level That Are Related to Treatment	Blood samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of blood bilirubin levels. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Other	Number of Participants With Abnormal Laboratory Values for Urine Creatinine level That Are Related to Treatment	Urine samples will be collected at baseline and at 240 minutes on days 1 and 4 of the study to measure safety labs. Safety labs will include measurement of urine creatinine levels. This will help determine if the principal investigator should take any action to remove the participant from the study.	Baseline, 240 min on Day 1 and Day 4	Yes
Primary	Blood and urine measurements of isotopic [13C]-urea concentration	At time zero of the study, participants will be given an intravenous bolus infusion of [13C]-urea. The concentration of [13C]-urea in the body will be measured/traced throughout the duration of the study (4 hours) by collecting blood and urine samples at specified time points. Blood [13C]-urea will be measured at time points 0, 30, 60, 90, 120, 180, and 240 minutes. Urine [13C]-urea will be measured at time points 0 and 240 minutes.	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	No
Primary	Blood measurements of isotopic [13-CO2] concentration	At time zero of the study, participants will receive an intravenous bolus infusion of [13C]-urea. The amount of metabolized [13C]-urea in the body will be measured throughout the duration of the study by collecting blood samples and analyzing them for [13CO2] concentration. Blood [13-CO2] will be measured at time points 0, 30, 60, 90, 120, 180, and 240 minutes.	0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4	No
Secondary	Blood and urine samples measuring urea concentration	The drug under study, Lithostat, is a bacterial urease inhibitor. Throughout the study, the investigators will measure the concentration of urea in blood and urine samples to get baseline urea measurements for the participant (no study drug) and to see how drug administration affects the levels of blood urea concentration (study drug). Blood urea measurement will occur at time points 0, 30, 60, 90, 120, 180, and 240 minutes. Urine urea measurement will occur at time points 0 and 240 minutes.	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	No
Secondary	Blood samples measuring ammonia concentration	Participants will have ammonia levels measured at various time points throughout the study. Ammonia is produced when urea is hydrolyzed by bacterial urease. The investigators predict that the administration of Lithostat, a gut bacterial urease inhibitor, will have an effect on the concentration of blood ammonia by using this study intervention. Blood ammonia will be measured at time points 0, 30, 60, 90, 120, 180, and 240 minutes.	0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4	No
Secondary	Blood plasma samples measuring glutamine concentration	The new indication proposed for the drug Lithostat, is for use in patients with urea cycle disorders. Elevated blood ammonia levels in patients with urea cycle disorders usually also corresponds to elevated blood glutamine levels as well. The investigators will collect blood samples to measure glutamine concentration at specified time points. Blood glutamine will be measured at time points 0, 30, 60, 90, 120, 180, and 240 minutes.	0, 30, 60, 90, 120, 180, 240 minutes on Day 1 and Day 4	No