Urea Cycle DisorderPhase 1/2NCT03181828
Manipulating the Gut Microbiome Study
A Phase 1/2 study testing Acetohydroxamic Acid Oral Tablet and No treatment in people with Urea Cycle Disorder, run by Nicholas Ah Mew at 1 site in United States.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Urea Cycle Disorder
- What is being tested?
- Acetohydroxamic Acid Oral Tablet and No treatment
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Mar 2017to 5 Jun 2018
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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).
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
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
Read the 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).
- Conditions
- Urea Cycle Disorder
- Being tested
- Acetohydroxamic Acid Oral Tablet, No treatment
- Keywords
- CPSI deficiency, OTC Deficiency, AS Deficiency, AL Deficiency
- Medical subject headings
- Urea Cycle Disorders, Inborn, Ornithine Carbamoyltransferase Deficiency Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Acetohydroxamic Acid Oral TabletDrug
Also called Lithostat
A single oral dose of 60 mg/kg acetohydroxamic acid rounded to the nearest 250 mg tablet.
No treatmentOther
No treatment
| Study group | Role | What they receive |
|---|---|---|
| Acetohydroxamic Acid Oral Tablet then No Intervention | Experimental | 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. Receives: Drug: Acetohydroxamic Acid Oral Tablet; Other: No treatment |
| No Intervention then Acetohydroxamic Acid Oral Tablet | Experimental | 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). Receives: Drug: Acetohydroxamic Acid Oral Tablet; Other: No treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
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,
Measured: Time +0 minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of infused [13C] Urea IV
Secondary outcomes (1)
Blood [13C]-Urea
Concentration of urea labeled with Carbon-13
Measured: Time +O minutes, +30 minutes, +60 minutes, +90 minutes, +120 minutes, +180 minutes, and +240 minutes from time of [13C] Urea IV
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2017
- Study start24 Mar 2017
- Primary completion5 Jun 2018
- Study completion5 Jun 2018
Why it stopped: The incidence of AEs was higher than the IB reported.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Urea Cycle DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- 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)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nicholas Ah Mew
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Nicholas Ah Mew, Children's National Research Institute
- Investigators
- Nicholas Ah Mew, MD, Principal investigator, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03181828
- Sponsor's protocol ID
- #7230
- Status last verified
- Nov 2021
- First submitted
- 1 Jun 2017
- Last updated
- 15 Dec 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Manipulating the Gut Microbiome Study
- ClinicalTrials.gov ID
- NCT03181828
- Acronym / sponsor ID
- #7230
- Conditions
- Urea Cycle Disorder
- Keywords
- CPSI deficiency, OTC Deficiency, AS Deficiency, AL Deficiency
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The incidence of AEs was higher than the IB reported.
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Nicholas Ah MewUniversity, hospital or other
- Study start
- 24 Mar 2017 (actual)
- Primary completion
- 5 Jun 2018 (actual)
- Study completion
- 5 Jun 2018 (actual)
- First posted
- 9 Jun 2017 (actual)
- Results
- Posted 15 Dec 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Acetohydroxamic Acid Oral Tablet then No Intervention | Experimental | Drug: Acetohydroxamic Acid Oral Tablet, Other: No treatmentParticipants 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. |
| No Intervention then Acetohydroxamic Acid Oral Tablet | Experimental | Drug: Acetohydroxamic Acid Oral Tablet, Other: No treatmentParticipants 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). |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- For Group 1 (healthy adults):
- Ages 18-60 years
- Compliant with receiving medications orally and intravenously
- Compliant with providing blood and urine samples
- Ages 18-60 years
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acetohydroxamic Acid Oral TabletAlso: LithostatA single oral dose of 60 mg/kg acetohydroxamic acid rounded to the nearest 250 mg tablet. | Drug | Acetohydroxamic Acid Oral Tablet then No Intervention, No Intervention then Acetohydroxamic Acid Oral Tablet |
| No treatmentNo treatment | Other | Acetohydroxamic Acid Oral Tablet then No Intervention, No Intervention then Acetohydroxamic Acid Oral Tablet |
Primary outcome
Atom Percent Excess of 13CO2
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
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,
1 secondary outcome
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Dec 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nicholas Ah Mew, MD principal investigator
Children's National Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Acetohydroxamic Acid Oral Tablet and No treatment in people with Urea Cycle Disorder, run by Nicholas Ah Mew at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 15 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Dec 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Atom Percent Excess of 13CO2 (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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Dec 2021.