Manipulating the Gut Microbiome Study
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|ClinicalTrials.gov Identifier: NCT03181828|
Recruitment Status : Terminated (The incidence of AEs was higher than the IB reported.)
First Posted : June 9, 2017
Last Update Posted : April 5, 2019
|Condition or disease||Intervention/treatment||Phase|
|Urea Cycle Disorder||Drug: Acetohydroxamic Acid Oral Tablet [Lithostat]||Phase 1 Phase 2|
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).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||4 participants|
|Intervention Model:||Crossover Assignment|
|Intervention 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)|
|Official Title:||Manipulating the Gut Microbiome Study|
|Actual Study Start Date :||March 24, 2017|
|Actual Primary Completion Date :||June 5, 2018|
|Actual Study Completion Date :||June 5, 2018|
|No Intervention: Non- AHA|
Active Comparator: AHA
All subjects (healthy adults and UCD patients) will receive a single oral dose of 60 mg/kg acetohydroxamic acid during one of the treatment periods, based on the randomization assignment determining whether treatment occurs in the first or the second treatment cycle; doses will be rounded to the nearest 250 mg to coincide with the available dosage form since the tablets cannot be scored. Patients will be instructed to fast for 4 hours prior to the study; subsequently, the 13C-Urea tracer will be administered 60 minutes after the ingestion of the acetohydroxamic acid dose.
Drug: Acetohydroxamic Acid Oral Tablet [Lithostat]
Acetohydroxamic acid has been an FDA approved medication for the treatment of struvite nephrolithiasis for over 25 years. According to the prescribing information, about 150 patients, including children, have been treated, most for periods of more than 1 year.
- Blood 13CO2 [ Time Frame: Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV ]Difference in the time-averaged level of blood 13CO2 after a single bolus of intravenous [13C]-Urea,
- Blood [13C]-Urea [ Time Frame: Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV ]Differences in blood [13C]-Urea
- Blood Urea [ Time Frame: Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV ]Differences in blood Urea
- Blood Ammonia [ Time Frame: Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV ]Differences in blood Ammonia
- Blood Glutamine [ Time Frame: Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV ]Differences in blood Glutamine
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): NCT03181828
|United States, District of Columbia|
|Children's National Medical Center|
|Washington, District of Columbia, United States, 20010|
|Principal Investigator:||Nicholas Ah Mew, MD||Children's Research Institute|