Argininosuccinate Lyase DeficiencyNCT03064048
Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD
A study testing Neo-ASA in people with Argininosuccinate Lyase Deficiency and Urea Cycle Disorder, run by Baylor College of Medicine at 1 site in United States.
Trial summary
This is a study involving a dietary supplement. Patients with argininosuccinate lyase deficiency (ASLD) will be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 24 weeks, and then crossed-over to receive the other treatment for 24 weeks. Read more about this study
- Who is it for?
- Ages 6 to 50 years
- Conditions the study is for
- Argininosuccinate Lyase Deficiency, Urea Cycle Disorder, Urea Cycle Disorders, Inborn
- What is being tested?
- Neo-ASA
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Sep 2017to 31 Jan 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 6 to 50 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Age > 6 and <50 years
- Diagnosis of ASLD confirmed by biochemical OR enzymatic OR genetic testing
- Has a history of compliance with diet and treatment
- Negative pregnancy test and ability to use birth control method for the entire duration of the study (if the subject is of child-bearing potential)
- Males who enroll in the study (and their partners) should argee to use an acceptable form of birth control for the entire duration of the study
Who cannot join
- Clinical or laboratory abnormality of Grade 3 or greater according to the CTCAE (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity) at enrollment which, in the view of the investigator compromises safety. (Elevated plasma levels of aspartate and alanine aminotransferases, or low serum potassium will not be considered as exclusion criteria as these are phenotypic manifestations of ASLD.)
- Known hypersensitivity to Neo-ASA or nitrite
- Individuals currently being administered other investigational agents
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)
This is a study involving a dietary supplement. Patients with argininosuccinate lyase deficiency (ASLD) will be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 24 weeks, and then crossed-over to receive the other treatment for 24 weeks. The investigators will assess the effects of the supplement in domains of general cognition, memory, executive functioning, and fine motor functioning in individuals with ASLD.
Read the detailed description
Argininosuccinate lyase deficiency (ASLD; also known as argininosuccinic aciduria) is the second most common urea cycle disorder (UCD) and accounts for 15-20% of all disorders of ureagenesis. Individuals with ASLD can have unique clinical and physiologic characteristics as compared to other UCDs. Previous work from the members of the UCDC have shown that in spite of having fewer episodes of hyperammonemia as compared to those with proximal blockade of the urea cycle, individuals with ASLD can develop intellectual and learning disabilities. Neurocognitive deficits have been observed even in individuals without any documented hyperammonemia. Furthermore, hepatic abnormalities including hepatomegaly, hepatic injury, fibrosis and even frank cirrhosis, and vascular issues like hypertension are well known in the disorder. Previous work from the members of the UCDC has demonstrated a tissue- and molecular-specific role for ASL in the generation of NO. ASL is not only required for the synthesis of L-arginine, the substrate for the synthesis of NO, but is also an integral member of a complex that is critical for synthesis of NO from arginine. Loss of ASL can thus lead to systemic and tissue-specific NO deficiencies, which could potentially contribute to the complex phenotype including the neurocognitive deficits. A rational therapeutic option would hence be to use a NOS-independent NO supplement.
The purpose of this study is to determine whether a dietary NO supplement, Neo-ASA, would improve general cognition, memory, executive functioning, fine motor functioning, and attention in individuals with ASLD. In this single-center trial, double-blind, randomized, placebo-controlled, crossover study, individuals with ASLD will be assigned to receive a medication containing NO dietary supplement for 24 weeks and a placebo for 24 weeks. General cognition, memory, executive functioning, and fine motor functioning will be assessed and compared at the end of treatment with placebo and Neo-ASA.
- Conditions
- Argininosuccinate Lyase Deficiency, Urea Cycle Disorder, Urea Cycle Disorders, Inborn, Argininosuccinic Aciduria
- Being tested
- Neo-ASA, Placebo
- Keywords
- Argininosuccinate Lyase Deficiency, Urea Cycle Disorder
- Medical subject headings
- Argininosuccinic Aciduria, Urea Cycle Disorders, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Neo-ASADietary supplement
Dietary supplement with nitric oxide in the form of a lozenge called Neo-ASA.
PlaceboDietary supplement
Dietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA
| Study group | Role | What they receive |
|---|---|---|
| Neo-ASA | Active comparator | During this arm the participant will receive a lozenge with nitric oxide as a dietary supplement twice daily. Receives: Dietary Supplement: Neo-ASA |
| Placebo | Placebo comparator | During this arm the participant will receive a lozenge which will not contain nitric oxide as a dietary supplement twice daily. Receives: Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Delis-Kaplan Executive Function System - Tower subtest
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Stanford-Binet - 4th Edition: Bead Memory and Sentence Memory subtests
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Grip Strength
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Grooved Pegboard
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Wechsler Intelligence Scale for Children OR Wechsler Adult Intelligence Scale - 4th Edition (in subjects > 16 years of age)
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Tower of London Test
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Conners Continuous Performance Test - 3rd Edition Conners Continuous Performance Test - 3rd Edition
Change in the scores from baseline to 24 weeks with drug vs placebo
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Feb 2017
- Study start15 Sep 2017
- Primary completion31 Jan 2023
- Study completion31 Jan 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Argininosuccinate Lyase DeficiencyStudies of the same condition, open and under way.
- More trials run by Baylor College of MedicineThe sponsor's other registered studies.
- 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Active Comparator: Nitric oxide supplement Active Comparator will l not contain nitric oxide supplement. Placebo Comparator: Placebo Placebo will not contain nitric oxide supplement.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baylor College of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Rare Diseases Clinical Research Network, Neogenis Laboratories
- Responsible party
- Principal investigator, Sandesh Chakravarthy Sreenath Nagamani, Baylor College of Medicine
- Investigators
- Sandesh C Nagamani, M.D., Principal investigator, Baylor College of MedicineBrendan Lee, M.D., PhD, Principal investigator, Baylor College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03064048
- Sponsor's protocol ID
- H-40143
- Status last verified
- Feb 2023
- First submitted
- 10 Feb 2017
- Last updated
- 27 Feb 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: According to the policy of the National Institutes of Health (one of the study sponsors) research data may be put in a secure, limited-access database known as dbGaP. The data will include any genetic test results as well as other information about medical problems. There will be NO identifiers included (no name, data of birth, address, social security number, etc.). Access to this information is restricted by the National Institutes of Health. Only doctors and scientists who get approval from the National Institutes of Health can access this de-identified data.
Publications
Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.
PubMed 22541557Nagamani SCS, Burrage LC, Lee B. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [updated 2025 Aug 14]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK51784/
PubMed 21290785Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. 2011 Nov 13;17(12):1619-26. doi: 10.1038/nm.2544.
PubMed 22081021
Study at a glance
From the registry record, last updated by the sponsor on 27 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)
- ClinicalTrials.gov ID
- NCT03064048
- Acronym / sponsor ID
- H-40143
- Conditions
- Argininosuccinate Lyase Deficiency, Urea Cycle Disorder, Urea Cycle Disorders, Inborn, Argininosuccinic Aciduria
- Keywords
- Argininosuccinate Lyase Deficiency, Urea Cycle Disorder
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Baylor College of MedicineUniversity, hospital or other
- Collaborators
- Rare Diseases Clinical Research Network, Neogenis Laboratories
- Study start
- 15 Sep 2017 (actual)
- Primary completion
- 31 Jan 2023 (actual)
- Study completion
- 31 Jan 2023 (actual)
- First posted
- 24 Feb 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a study involving a dietary supplement. Patients with argininosuccinate lyase deficiency (ASLD) will be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 24 weeks, and then crossed-over to receive the other treatment for 24 weeks. The investigators will assess the effects of the supplement in domains of general cognition, memory, executive functioning, and fine motor functioning in individuals with ASLD.
Detailed description
Argininosuccinate lyase deficiency (ASLD; also known as argininosuccinic aciduria) is the second most common urea cycle disorder (UCD) and accounts for 15-20% of all disorders of ureagenesis. Individuals with ASLD can have unique clinical and physiologic characteristics as compared to other UCDs. Previous work from the members of the UCDC have shown that in spite of having fewer episodes of hyperammonemia as compared to those with proximal blockade of the urea cycle, individuals with ASLD can develop intellectual and learning disabilities. Neurocognitive deficits have been observed even in individuals without any documented hyperammonemia. Furthermore, hepatic abnormalities including hepatomegaly, hepatic injury, fibrosis and even frank cirrhosis, and vascular issues like hypertension are well known in the disorder. Previous work from the members of the UCDC has demonstrated a tissue- and molecular-specific role for ASL in the generation of NO. ASL is not only required for the synthesis of L-arginine, the substrate for the synthesis of NO, but is also an integral member of a complex that is critical for synthesis of NO from arginine. Loss of ASL can thus lead to systemic and tissue-specific NO deficiencies, which could potentially contribute to the complex phenotype including the neurocognitive deficits. A rational therapeutic option would hence be to use a NOS-independent NO supplement.
The purpose of this study is to determine whether a dietary NO supplement, Neo-ASA, would improve general cognition, memory, executive functioning, fine motor functioning, and attention in individuals with ASLD. In this single-center trial, double-blind, randomized, placebo-controlled, crossover study, individuals with ASLD will be assigned to receive a medication containing NO dietary supplement for 24 weeks and a placebo for 24 weeks. General cognition, memory, executive functioning, and fine motor functioning will be assessed and compared at the end of treatment with placebo and Neo-ASA.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Active Comparator: Nitric oxide supplement Active Comparator will l not contain nitric oxide supplement. Placebo Comparator: Placebo Placebo will not contain nitric oxide supplement.
| Arm | Type | Receives |
|---|---|---|
| Neo-ASA | Active comparator | Dietary Supplement: Neo-ASADuring this arm the participant will receive a lozenge with nitric oxide as a dietary supplement twice daily. |
| Placebo | Placebo comparator | Dietary Supplement: PlaceboDuring this arm the participant will receive a lozenge which will not contain nitric oxide as a dietary supplement twice daily. |
Who may qualify
- Ages
- 6 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Age > 6 and <50 years
- Diagnosis of ASLD confirmed by biochemical OR enzymatic OR genetic testing
- Has a history of compliance with diet and treatment
- Negative pregnancy test and ability to use birth control method for the entire duration of the study (if the subject is of child-bearing potential)
- Males who enroll in the study (and their partners) should argee to use an acceptable form of birth control for the entire duration of the study
Key exclusion criteria (3 listed)
- Clinical or laboratory abnormality of Grade 3 or greater according to the CTCAE (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity) at enrollment which, in the view of the investigator compromises safety. (Elevated plasma levels of aspartate and alanine aminotransferases, or low serum potassium will not be considered as exclusion criteria as these are phenotypic manifestations of ASLD.)
- Known hypersensitivity to Neo-ASA or nitrite
- Individuals currently being administered other investigational agents
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 |
|---|---|---|
| Neo-ASADietary supplement with nitric oxide in the form of a lozenge called Neo-ASA. | Dietary supplement | Neo-ASA |
| PlaceboDietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA | Dietary supplement | Placebo |
Primary outcome
Delis-Kaplan Executive Function System - Tower subtest
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Stanford-Binet - 4th Edition: Bead Memory and Sentence Memory subtests
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Grip Strength
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Grooved Pegboard
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Wechsler Intelligence Scale for Children OR Wechsler Adult Intelligence Scale - 4th Edition (in subjects > 16 years of age)
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Tower of London Test
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Conners Continuous Performance Test - 3rd Edition Conners Continuous Performance Test - 3rd Edition
Time frame: 24 weeks
Change in the scores from baseline to 24 weeks with drug vs placebo
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Feb 2023.
- Background: PubMed 22541557Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.
- Background: PubMed 21290785Nagamani SCS, Burrage LC, Lee B. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [updated 2025 Aug 14]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK51784/
- Background: PubMed 22081021Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. 2011 Nov 13;17(12):1619-26. doi: 10.1038/nm.2544.
- Individual participant dataSharing planned: Yes. According to the policy of the National Institutes of Health (one of the study sponsors) research data may be put in a secure, limited-access database known as dbGaP. The data will include any genetic test results as well as other information about medical problems. There will be NO identifiers included (no name, data of birth, address, social security number, etc.). Access to this information is restricted by the National Institutes of Health. Only doctors and scientists who get approval from the National Institutes of Health can access this de-identified data.
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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.
Sandesh C Nagamani, M.D. principal investigator
Baylor College of Medicine
Brendan Lee, M.D., PhD principal investigator
Baylor College of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Neo-ASA in people with Argininosuccinate Lyase Deficiency and Urea Cycle Disorder, run by Baylor College of Medicine 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 5 inclusion and 3 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 27 Feb 2023. 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. Some participants in this study may receive a placebo. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Delis-Kaplan Executive Function System - Tower subtest (time frame: 24 weeks). The study lists 7 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 NCT03064048, 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 27 Feb 2023.