- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03064048
Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD
Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Mary A Mullins, RN
- Phone Number: 832-822-4263
- Email: mullins@bcm.edu
Study Contact Backup
- Name: Sandesh C Nagamani, M.D.
- Email: nagamani@bcm.edu
Study Locations
-
-
Texas
-
Houston, Texas, United States, 77030
- Baylor College of Medicine
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Neo-ASA
During this arm the participant will receive a lozenge with nitric oxide as a dietary supplement twice daily.
|
Dietary supplement with nitric oxide in the form of a lozenge called Neo-ASA.
|
Placebo Comparator: Placebo
During this arm the participant will receive a lozenge which will not contain nitric oxide as a dietary supplement twice daily.
|
Dietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Delis-Kaplan Executive Function System - Tower subtest
Time Frame: 24 weeks
|
Change in the scores from baseline to 24 weeks with drug vs placebo
|
24 weeks
|
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
|
24 weeks
|
Grip Strength
Time Frame: 24 weeks
|
Change in the scores from baseline to 24 weeks with drug vs placebo
|
24 weeks
|
Grooved Pegboard
Time Frame: 24 weeks
|
Change in the scores from baseline to 24 weeks with drug vs placebo
|
24 weeks
|
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
|
24 weeks
|
Tower of London Test
Time Frame: 24 weeks
|
Change in the scores from baseline to 24 weeks with drug vs placebo
|
24 weeks
|
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
|
24 weeks
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General 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.
- Nagamani SCS, Erez A, Lee B. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [updated 2019 Mar 28]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK51784/
- Erez 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Metabolic Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Genetic Diseases, Inborn
- Metabolism, Inborn Errors
- Brain Diseases, Metabolic
- Brain Diseases, Metabolic, Inborn
- Amino Acid Metabolism, Inborn Errors
- Disease
- Urea Cycle Disorders, Inborn
- Argininosuccinic Aciduria
Other Study ID Numbers
- H-40143
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Urea Cycle Disorders, Inborn
-
Horizon Therapeutics, LLCCompletedUrea Cycle DisorderUnited States, Spain, Italy, Switzerland
-
Istanbul University - Cerrahpasa (IUC)CompletedUrea Cycle Disorder | Lysinuric Protein IntoleranceTurkey
-
Horizon Therapeutics, LLCTerminatedUrea Cycle DisorderUnited States
-
Nutricia ResearchCompletedInborn Errors of Metabolism | Urea Cycle DisorderUnited States
-
SynlogicCompletedHealthy Volunteer | Urea Cycle DisorderUnited States
-
Kaleido BiosciencesTerminatedUrea Cycle DisorderBelgium, United States, Spain, United Kingdom, Germany, Switzerland, Turkey
-
University of AarhusRecruiting
-
Baylor College of MedicineSeattle Children's Hospital; University of California, San FranciscoCompleted
-
HLB Cell Co., Ltd.WithdrawnUrea Cycle DisorderKorea, Republic of
Clinical Trials on Neo-ASA
-
Dr Kundan Singh ChufalActive, not recruitingEsophageal NeoplasmAustralia, India
-
Neuracle Medical Technology(Shanghai) Co.,Ltd.Beijing Tiantan Hospital; Chinese PLA General Hospital; Xuanwu Hospital, BeijingNot yet recruiting
-
Neo Medical SAConfinisCPMActive, not recruitingTrauma | Degenerative Disc Disease | Spinal Stenosis | Spondylolisthesis | Spinal Tumor | Pseudoarthrosis of SpineGermany, Spain
-
Sun Yat-sen UniversityThe First Affiliated Hospital of Guangzhou Medical University; Sixth Affiliated...RecruitingHepatectomy | Primary Liver Cancer | Immunotherapy | Radiofrequency AblationChina
-
The First People's Hospital of LianyungangHengrui Yuanzheng Bio-Technology Co., Ltd.Unknown
-
Symetis SATerminated
-
University of WashingtonEunice Kennedy Shriver National Institute of Child Health and Human Development...RecruitingPerinatal Death | Neonatal DeathKenya
-
NantBioScience, Inc.Active, not recruitingMelanoma | Breast Cancer | Colorectal Cancer | Pancreatic Cancer | Non Small Cell Lung Cancer | Head and Neck Squamous Cell Carcinoma | Liver CancerUnited States