Brain Diseases, Metabolic, InbornNCT00472732

Neurologic Injuries in Adults With Urea Cycle Disorders

An observational study of Brain Diseases, Metabolic, Inborn and Urea Cycle Disorder, run by Andrea Gropman at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Urea cycle disorders (UCDs) are a group of rare inherited metabolism disorders. The purpose of this study is to evaluate how UCD-related neurologic injuries affect adults with one of the most common types of UCD. Read more about this study

Who is it for?: Ages 18 to 60 yearsHealthy volunteers can take part
Conditions the study is for: Brain Diseases, Metabolic, Inborn, Urea Cycle Disorder, Ornithine Transcarbamylase Deficiency
How many people: 46 participants
Where: 2 sitesUnited States
Study dates: Mar 2007to Jul 2010
Phase: Observational
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

Study population: Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD

Who may be able to join

Diagnosis of OTCD or heterozygote state of OTCD by metabolic or molecular means. Female participants must be clinically stable and heterozygous for OTCD. Male participants must be hemizygous for late onset OTCD.
No known medical or metabolic disorder
IQ of at least 80
Willing to travel to study site
English-speaking
Age between 18 and 60 years

Who cannot join

Currently being treated for an acute illness
History of neuropsychiatric drug use
Unable to undergo MRI scanning without being sedated
Unable to participate in neurocognitive and/or motor testing
Metal device in body that might interfere with MRI scanning
Pregnancy or breastfeeding

Trial locations and contacts

2 sites in 1 country.

United States2 sites

George Washington University School of Medicine
Washington D.C., District of Columbia, 20037
Georgetown University
Washington D.C., District of Columbia, 20057

Other trials in United States

About this study

Official title: Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy

Read the detailed description

UCDs are a group of rare genetic diseases that affect how protein is broken down in the body. The cause of UCDs is a deficiency in one of eight enzymes responsible for removing ammonia, a waste product of protein metabolism, from the bloodstream. Normally, ammonia is converted into urea and then removed from the body in the form of urine. However, in people with UCDs, ammonia accumulates unchecked and is not removed from the body. Toxic levels of ammonia can build up and cause irreversible neurologic damage that can affect metabolism, cognition, sensation, and movement. This study will focus on the most common enzyme disorder among UCDs, ornithine transcarbamylase deficiency (OTCD), a disorder inherited from mothers. Using different types of magnetic resonance imaging (MRI), this study will evaluate how UCD-related neurologic injuries affect metabolism, cognition, sensation, and movement in adults with OTCD.

Participants in this study will attend an initial study visit that will include a review of medical history, current symptoms, impairments, and diet history; urine and blood collection; a physical exam; a full neurological exam; and cognitive and motor testing. During this visit, participants will undergo imaging studies and additional cognitive and motor testing over a 2- to 3-day period. This will include standard MRI studies and four sessions consisting of functional MRI (fMRI), diffusion tensor imaging, and 1H magnetic resonance spectroscopy. For the fMRI study, participants perform various motor and behavioral tasks while in the imaging scanner. Magnetic resonance spectroscopy (MRS) is used to study and evaluate the chemical makeup of specific brain areas. Diffusion tensor imaging is used to assess myelination of major brain pathways and their alteration in disease states. This study will involve one-time participation. There will be no follow-up visits for this study.

Conditions: Brain Diseases, Metabolic, Inborn, Urea Cycle Disorder, Ornithine Transcarbamylase Deficiency
Keywords: UCD, OTCD, Ammonia, Urea Metabolism, Inborn Errors
Medical subject headings: Brain Diseases, Metabolic, Inborn, 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.

Study groups in NCT00472732
Study group	Role	What they receive
1		Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD
2		Healthy males or females without known medical or metabolic disorder (control group)

What is being measured

The primary outcome is the main question the study is designed to answer.

Concentration of Glutamine and Myoinositol by MRS
Concentration based on area under curve on 1H MRS and quantitated by LCModel. A metabolite's tissue concentration is related to the integrated amplitude of the MRS signal it produces. Integrated amplitude is the area under the MRS signal curve. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. This means, 257 free induction decays. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point.
Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM).
Measured: one time measurement at study baseline
Functional MRI Activation in N-Back Tast
Measure of blood oxygen level dependent (BOLD) signal of OTCD patients and healthy controls during an N-Back task comparing 2-back and 1-back conditions. This contrast was created for each participant using SPM and then entered into a group analysis in which we compare percent signal change between groups. Therefore, we never see BOLD signal change at the individual level, which is why we never see "scores" or numbers at the individual level and we cannot calculate a measure of dispersion for this data.
Measured: one time measurement at study baseline
Fractional Anisotropy
Measure of white matter integrity in OTCD Patients and Controls in frontal white matter. Fractional anisotropy values fall on a scale of 0 to 1, with 0 meaning that the diffusion of water is isotropic and unrestricted, or equally restricted, in all directions and with 1 meaning that diffusion occurs along only one axis and is fully restricted along all other directions. Scores closer to 1 are associated with intact white matter while scores closer to 0 are associated with white matter damage.
Measured: one time measurement at study baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 2007Jul 2010

First posted14 May 2007 (estimated)
Study startMar 2007
Primary completionJul 2009
Study completionJul 2010

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.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Brain Diseases, Metabolic, InbornStudies 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: Observational
Observational model: Cohort
Time perspective: Prospective
Enrolment: 46 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00472732
Sponsor's protocol ID: RDCRN 5104
Other IDs: U54RR019453
Status last verified: May 2015
First submitted: 11 May 2007
Last updated: 24 Jun 2015
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004 Jan;55(1):80-6. doi: 10.1002/ana.10794.
PubMed 14705115
Kurihara A, Takanashi Ji, Tomita M, Kobayashi K, Ogawa A, Kanazawa M, Yamamoto S, Kohno Y. Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency. Brain Dev. 2003 Jan;25(1):40-4. doi: 10.1016/s0387-7604(02)00153-5.
PubMed 12536032
McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. 2000 Aug 14;93(4):313-9. doi: 10.1002/1096-8628(20000814)93:43.0.co;2-m.
PubMed 10946359

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingObservational study
Long-term Follow-up (LTFU) Study of Participants in Any iECURE Protocol Using an Investigational Product (IP)
Ornithine Transcarbamylase Deficiency, Ornithine Transcarbamylase Deficiency Disease
Active, not recruitingPhase 1/2
Gene Transfer Clinical Trial for Infantile and Late Infantile Krabbe Disease Treated Previously With HSCT
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Market Research of a Slow Release Protein Substitute for the Dietary Management of PKU
Phenylketonuria (PKU) and Hyperphenylalaninemia, Brain Diseases, Metabolic, Inborn
Active, not recruitingPhase 3
An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
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RecruitingObservational study
A Long-Term Observational Study of Patients With Fucosidosis
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All Brain Diseases, Metabolic, Inborn trials

Study at a glance

From the registry record, last updated by the sponsor on 24 Jun 2015. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy
ClinicalTrials.gov ID: NCT00472732
Acronym / sponsor ID: RDCRN 5104
Conditions: Brain Diseases, Metabolic, Inborn, Urea Cycle Disorder, Ornithine Transcarbamylase Deficiency
Keywords: UCD, OTCD, Ammonia, Urea Metabolism, Inborn Errors
Study type: Observational
Recruitment status: Completed
Enrolment: 46 participants (actual)
Lead sponsor: Andrea GropmanUniversity, hospital or other
Collaborators: Office of Rare Diseases (ORD), Rare Diseases Clinical Research Network, National Center for Research Resources (NCRR)
Study start: Mar 2007
Primary completion: Jul 2009 (actual)
Study completion: Jul 2010 (actual)
First posted: 14 May 2007 (estimated)
Results: Posted 29 May 2015

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Observational model: Cohort
Time perspective: Prospective
Number of arms: 2

Arm	Type	Receives
1	–	–Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD
2	–	–Healthy males or females without known medical or metabolic disorder (control group)

Who may qualify

Ages: 18 to 60 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult
Study population: Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD

Key inclusion criteria (6 listed)

Diagnosis of OTCD or heterozygote state of OTCD by metabolic or molecular means. Female participants must be clinically stable and heterozygous for OTCD. Male participants must be hemizygous for late onset OTCD.
No known medical or metabolic disorder
IQ of at least 80
Willing to travel to study site
English-speaking

Key exclusion criteria (6 listed)

Currently being treated for an acute illness
History of neuropsychiatric drug use
Unable to undergo MRI scanning without being sedated
Unable to participate in neurocognitive and/or motor testing
Metal device in body that might interfere with MRI scanning

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Primary outcome

Concentration of Glutamine and Myoinositol by MRS
Time frame: one time measurement at study baseline
Concentration based on area under curve on 1H MRS and quantitated by LCModel. A metabolite's tissue concentration is related to the integrated amplitude of the MRS signal it produces. Integrated amplitude is the area under the MRS signal curve. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. This means, 257 free induction decays. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point. Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM).
Functional MRI Activation in N-Back Tast
Time frame: one time measurement at study baseline
Measure of blood oxygen level dependent (BOLD) signal of OTCD patients and healthy controls during an N-Back task comparing 2-back and 1-back conditions. This contrast was created for each participant using SPM and then entered into a group analysis in which we compare percent signal change between groups. Therefore, we never see BOLD signal change at the individual level, which is why we never see "scores" or numbers at the individual level and we cannot calculate a measure of dispersion for this data.
Fractional Anisotropy
Time frame: one time measurement at study baseline
Measure of white matter integrity in OTCD Patients and Controls in frontal white matter. Fractional anisotropy values fall on a scale of 0 to 1, with 0 meaning that the diffusion of water is isotropic and unrestricted, or equally restricted, in all directions and with 1 meaning that diffusion occurs along only one axis and is fully restricted along all other directions. Scores closer to 1 are associated with intact white matter while scores closer to 0 are associated with white matter damage.

Results and safety

Results posted to the registry on 29 May 2015, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Female Carriers of Ornithine Transcarbamylase Deficiency (OTCD	24	24
Healthy Males or Females Without Known Medical or Metabolic di	22	22

Primary outcome: Concentration of Glutamine and Myoinositol by MRS

Time frame: one time measurement at study baseline. Mean (Standard Deviation). Unit: mM

Measure	OTCD Patients n = 24	Healthy Controls n = 22
Glutamine in PCGM	4.97 (2.08)	3.66 (1.36)
Myoinositol in PCGM	3.78 (0.82)	4.50 (0.43)
Glutamine in PWM	2.13 (1.22)	1.09 (0.75)
Myoinositol in PWM	2.27 (0.77)	2.86 (0.38)

OTCD Patients vs Healthy Controls: p = 0.003, t-test, 2 sided
OTCD Patients vs Healthy Controls: p <0.001, t-test, 2 sided
OTCD Patients vs Healthy Controls: p = 0.001, t-test, 2 sided

Primary outcome: Functional MRI Activation in N-Back Tast

Time frame: one time measurement at study baseline. Number. Unit: percent signal change

Measure	OTCD Patients n = 19	Healthy Controls n = 21
Dorsolateral prefrontal cortex (BA 10)	0.21	0.04
Dorsolateral prefrontal cortex (BA 46)	0.22	0.15
Anterior cingulate cortex (BA 32)	0.515	0.28

OTCD Patients vs Healthy Controls: p <0.05, t-test, 2 sided

Population analysed: Five OTCD patients and one healthy control were excluded due to excessive head motion.

Primary outcome: Fractional Anisotropy

Time frame: one time measurement at study baseline. Mean (Standard Deviation). Unit: units on a scale

Measure	OTCD Patients n = 19	Healthy Controls n = 18
Value	0.247 (0.016)	0.274 (0.015)

OTCD Patients vs Healthy Controls: p <0.001, t-test, 2 sided

Population analysed: Five OTCD Patients and four healthy controls were excluded due to excessive head motion.

Adverse events

Time frame: Entire study. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
OTCD Patients	0 of 24 (0%)	0 of 24 (0%)	Not reported
Healthy Controls	0 of 22 (0%)	0 of 22 (0%)	Not reported

Limitations and caveats (from the sponsor): This study examined the neurobiological differences between OTCD patients and controls. This was, however, not a clinical trial, since participants received no form of drug therapy or treatment as part of this study.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2015.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 14705115Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004 Jan;55(1):80-6. doi: 10.1002/ana.10794.
Background: PubMed 12536032Kurihara A, Takanashi Ji, Tomita M, Kobayashi K, Ogawa A, Kanazawa M, Yamamoto S, Kohno Y. Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency. Brain Dev. 2003 Jan;25(1):40-4. doi: 10.1016/s0387-7604(02)00153-5.
Background: PubMed 10946359McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. 2000 Aug 14;93(4):313-9. doi: 10.1002/1096-8628(20000814)93:43.0.co;2-m.

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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.

Andrea Gropman, MD study chair

Children's National Research Institute

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

An observational study of Brain Diseases, Metabolic, Inborn and Urea Cycle Disorder, run by Andrea Gropman at 2 sites 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 6 inclusion and 6 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: finished, as of the sponsor's last update on 24 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites 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.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 May 2015). 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?

Concentration of Glutamine and Myoinositol by MRS (time frame: one time measurement at study baseline). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00472732, which also lists 3 linked publications.

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 24 Jun 2015; AzTrials last refreshed its copy on 6 Nov 2026.