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Urease Inhibitor Drug Treatment for Urea Cycle Disorders

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ClinicalTrials.gov Identifier: NCT02670889
Recruitment Status : Not yet recruiting
First Posted : February 2, 2016
Last Update Posted : August 25, 2016
Sponsor:
Collaborators:
Data Management and Coordinating Center (DMCC)
Children's Hospital of Philadelphia
Information provided by (Responsible Party):
Nicholas Ah Mew, Children's Research Institute

Brief 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.

Condition or disease Intervention/treatment Phase
Ornithine Transcarbamylase Deficiency Argininosuccinate Synthetase Deficiency (Citrullinemia) Argininosuccinic Acid Lyase Deficiency (Argininosuccinic Aciduria) Carbamyl-Phosphate Synthase I Deficiency Drug: Acetohydroxamic Acid Drug: Isotopic Intravenous [13C]-Urea Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Manipulating the Gut Microbiome in Urea Cycle Disorders
Study Start Date : November 2016
Estimated Primary Completion Date : March 2018
Estimated Study Completion Date : March 2019


Arm Intervention/treatment
Experimental: Treatment with AHA
Study day using acetohydroxamic acid (with experimental drug) Safety labs will be collected prior to administering acetohydroxamic acid (AHA, experimental drug) to participants. The investigators will give the participant one dose of the AHA (dose: 60 mg/kg). 1 hour after taking the AHA, the participant will receive a single dose of Isotopic Intravenous [13C]-Urea through a different IV which will be inserted into the opposite arm and removed after the administration of the isotope. Over the next 4 hours, the investigators will collect blood samples to measure safety labs and various biomarkers. Urine samples will also be collected.
Drug: Acetohydroxamic Acid
Other Names:
  • Lithostat
  • AHA

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

Baseline Measurements without AHA (Study Drug)
Study day without the use of acetohydroxamic acid (no experimental drug) Procedures are identical except for the administration of AHA, which will not occur.
Drug: Isotopic Intravenous [13C]-Urea
Used to trace 13CO2 and 13C-urea in the blood.




Primary Outcome Measures :
  1. 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 ]
    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.

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


Secondary Outcome Measures :
  1. 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 ]
    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.

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

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


Other Outcome Measures:
  1. Number of Participants With Abnormal Laboratory Values for Blood Hemoglobin That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.

  2. Number of Participants With Abnormal Laboratory Values for White Blood Count That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.

  3. Number of Participants With Abnormal Laboratory Values for Blood Platelet Count That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.

  4. Number of Participants With Abnormal Laboratory Values for Blood AST level That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.

  5. Number of Participants With Abnormal Laboratory Values for Blood ALT level That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.

  6. Number of Participants With Abnormal Laboratory Values for Blood Bilirubin level That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.

  7. Number of Participants With Abnormal Laboratory Values for Urine Creatinine level That Are Related to Treatment [ Time Frame: Baseline, 240 min on Day 1 and Day 4 ]
    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.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02670889


Contacts
Contact: Nicholas Ah Mew, MD 202-476-5863 NAhMew@childrensnational.org
Contact: Lillian Assatourian, BS 202-476-6137 lassatouri@childrensnational.org

Sponsors and Collaborators
Nicholas Ah Mew
Data Management and Coordinating Center (DMCC)
Children's Hospital of Philadelphia
Investigators
Study Chair: Nicholas Ah Mew, MD Children's National Health System
Principal Investigator: Nicholas Ah Mew, MD Children's National Health System
Principal Investigator: Marshall L Summar, MD Children's National Health System

Responsible Party: Nicholas Ah Mew, Principal Investigator, Children's Research Institute
ClinicalTrials.gov Identifier: NCT02670889     History of Changes
Other Study ID Numbers: CNMC 7230, U54-HD061221
First Posted: February 2, 2016    Key Record Dates
Last Update Posted: August 25, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Nicholas Ah Mew, Children's Research Institute:
Urea Cycle Disorder

Additional relevant MeSH terms:
Urea Cycle Disorders, Inborn
Ornithine Carbamoyltransferase Deficiency Disease
Citrullinemia
Argininosuccinic Aciduria
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Genetic Diseases, X-Linked
Acetohydroxamic acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action