Clinical trial NCT03064048: Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD
Official title: Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Argininosuccinate Lyase Deficiency
Urea Cycle Disorder
Urea Cycle Disorders, Inborn
Argininosuccinic Aciduria
Keywords: Argininosuccinate Lyase Deficiency
Urea Cycle Disorder
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: Neogenis Laboratories
First posted: 2017-02-24
Enrollment: 16
Sex: ALL
Minimum age (years): 6
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: Inclusion Criteria:

1. Age \> 6 and \<50 years
2. Diagnosis of ASLD confirmed by biochemical OR enzymatic OR genetic testing
3. Has a history of compliance with diet and treatment
4. 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)
5. 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:

1. 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.)
2. Known hypersensitivity to Neo-ASA or nitrite
3. Individuals currently being administered other investigational agents

Primary outcomes:
measure: Delis-Kaplan Executive Function System - Tower subtest
timeFrame: 24 weeks
measure: Stanford-Binet - 4th Edition: Bead Memory and Sentence Memory subtests
timeFrame: 24 weeks
measure: Grip Strength
timeFrame: 24 weeks
measure: Grooved Pegboard
timeFrame: 24 weeks
measure: Wechsler Intelligence Scale for Children OR Wechsler Adult Intelligence Scale - 4th Edition (in subjects > 16 years of age)
timeFrame: 24 weeks
measure: Tower of London Test
timeFrame: 24 weeks
measure: Conners Continuous Performance Test - 3rd Edition Conners Continuous Performance Test - 3rd Edition
timeFrame: 24 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Sandesh C Nagamani, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine
name: Brendan Lee, M.D., PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Nagamani SCS, Erez A, Lee B. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [updated 2019 Mar 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK51784/
citation: 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.