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Manipulating the Gut Microbiome Study

Primary Purpose

Urea Cycle Disorder

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Acetohydroxamic Acid Oral Tablet
No treatment
Sponsored by
Nicholas Ah Mew
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Urea Cycle Disorder focused on measuring CPSI deficiency, OTC Deficiency, AS Deficiency, AL Deficiency

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • For Group 1 (healthy adults):
  • Ages 18-60 years
  • Compliant with receiving medications orally and intravenously
  • Compliant with providing blood and urine samples

For Group 2 (adult UCD patients):

  • Ages 18-60 years
  • 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:

  • For both Group 1 and Group 2:
  • 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

Sites / Locations

  • Children's National Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Acetohydroxamic Acid Oral Tablet then No Intervention

No Intervention then Acetohydroxamic Acid Oral Tablet

Arm Description

Participants receive a single oral dose of 60 mg/kg acetohydroxamic acid (rounded to the nearest 250 mg) in the fasted state on the morning of the study. After completion of the 4-h study, participants then enter a wash-out period of 3 days. Participants then completed an identical 4-h study in the fasted state without acetohydroxamic acid.

Participants completed a 4-h study in the fasted state without acetohydroxamic acid. 3 days later, participants then completed an identical 4-h study in the fasted state, after having received a single oral dose of 60 mg/kg acetohydroxamic acid (rounded to the nearest 250 mg).

Outcomes

Primary Outcome Measures

Atom Percent Excess of 13CO2
Difference in the % enrichment of Carbon-13 in blood CO2 as compared to baseline measurement, at sequential time points, after a single bolus of intravenous [13C]-Urea,

Secondary Outcome Measures

Blood [13C]-Urea
Concentration of urea labeled with Carbon-13

Full Information

First Posted
June 1, 2017
Last Updated
November 18, 2021
Sponsor
Nicholas Ah Mew
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1. Study Identification

Unique Protocol Identification Number
NCT03181828
Brief Title
Manipulating the Gut Microbiome Study
Official Title
Manipulating the Gut Microbiome Study
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Terminated
Why Stopped
The incidence of AEs was higher than the IB reported.
Study Start Date
March 24, 2017 (Actual)
Primary Completion Date
June 5, 2018 (Actual)
Study Completion Date
June 5, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Nicholas Ah Mew

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The objective 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
Detailed Description
This project will study the efficacy and safety of the pharmacologic blockade of urease in the nitrogen salvage pathway of intestinal microbes in subjects with partial urea cycle disorders. Additional trapping of ammonia as excretable urea may result in improved nitrogen excretion and reduced ammonia levels. Urea cycle disorders (UCDs) are a group of disorders resulting from a complete or partial deficiency of one of the 6 enzymes or 2 transporters that comprise the urea cycle, the essential biochemical pathway which converts toxic ammonia into urea. These disorders have as a common feature, a reduced or complete inability to convert ammonia into urea, thereby resulting in high ammonia levels, or hyperammonemia. If untreated, hyperammonemia may result acutely in lethargy and coma, and chronically in intellectual disability. Current treatment for hyperammonemia is suboptimal, thus the search for new treatments is critical. The urease inhibitor, acetohydroxamic acid (AHA, Lithostat®, Mission Pharmacal), is an FDA-approved product for another indication- the treatment of struvite nephrolithiasis in chronic urinary tract infections in both adults and children. It is known that many urea-splitting bacteria also exist in the gut, and that in healthy individuals, approximately 15-30% of blood urea is degraded via gut bacteria into ammonia3, which returns to the liver via the portal vein, only to be recycled into urea. This percentage of degraded urea may even be greater in patients with urea cycle disorders, who are on a low protein-diet4 and whose gastrointestinal contents thus likely have lower nitrogen content, promoting bacterial recycling of nitrogen from available urea. Additionally, urea hydrolysis has been shown to be greatest in infants5, precisely the age at which hyperammonemic episodes are the most frequent in UCD patients. We intend to study if AHA can inhibit gut bacteria degradation of urea, thereby reducing the quantity of ammonia returning to the liver. We intend to investigate this by studying subjects on two occasions at least 3 days apart: On the first occasion, subjects will receive an intravenous dose of 13C-urea. Following the intravenous bolus of 13C-urea, over the subsequent 4 hours, we will collect several sequential measurements of blood and urine biomarkers from an IV catheter placed in the other arm. The intent is to obtain baseline 13CO2 kinetics in the subject. On the second occasion, subjects will first receive an oral dose of AHA approximately 1 hour prior to the intravenous 13C-urea dose. Similar sequential measurements of blood and urine biomarkers will be performed. The intent is to observe a reduction in 13CO2 when AHA is administered. We intend to initially study a cohort of unaffected adult subjects. If successful, we will study adults with partial urea cycle disorders. This study will be conducted in the Clinical Research Center (CRC) of the Clinical and Translational Research Institute (CTSI) of Children's National Medical Center (CNMC).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urea Cycle Disorder
Keywords
CPSI deficiency, OTC Deficiency, AS Deficiency, AL Deficiency

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Model Description
This pilot randomized crossover study will first evaluate the impact of AHA versus non-AHA primarily on intestinal flora cleavage of an infused bolus of 13C-Urea and secondarily on other biomarkers in healthy adults before applying the same crossover design to UCD subjects.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Acetohydroxamic Acid Oral Tablet then No Intervention
Arm Type
Experimental
Arm Description
Participants receive a single oral dose of 60 mg/kg acetohydroxamic acid (rounded to the nearest 250 mg) in the fasted state on the morning of the study. After completion of the 4-h study, participants then enter a wash-out period of 3 days. Participants then completed an identical 4-h study in the fasted state without acetohydroxamic acid.
Arm Title
No Intervention then Acetohydroxamic Acid Oral Tablet
Arm Type
Experimental
Arm Description
Participants completed a 4-h study in the fasted state without acetohydroxamic acid. 3 days later, participants then completed an identical 4-h study in the fasted state, after having received a single oral dose of 60 mg/kg acetohydroxamic acid (rounded to the nearest 250 mg).
Intervention Type
Drug
Intervention Name(s)
Acetohydroxamic Acid Oral Tablet
Other Intervention Name(s)
Lithostat
Intervention Description
A single oral dose of 60 mg/kg acetohydroxamic acid rounded to the nearest 250 mg tablet.
Intervention Type
Other
Intervention Name(s)
No treatment
Intervention Description
No treatment
Primary Outcome Measure Information:
Title
Atom Percent Excess of 13CO2
Description
Difference in the % enrichment of Carbon-13 in blood CO2 as compared to baseline measurement, at sequential time points, after a single bolus of intravenous [13C]-Urea,
Time Frame
Time +0 minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of infused [13C] Urea IV
Secondary Outcome Measure Information:
Title
Blood [13C]-Urea
Description
Concentration of urea labeled with Carbon-13
Time Frame
Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: For Group 1 (healthy adults): Ages 18-60 years Compliant with receiving medications orally and intravenously Compliant with providing blood and urine samples For Group 2 (adult UCD patients): Ages 18-60 years 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: For both Group 1 and Group 2: 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicholas Ah Mew, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Manipulating the Gut Microbiome Study

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