Argininosuccinate Lyase Deficiency, Argininosuccinic Aciduria, Urea Cycle Disorder, Urea Cycle Disorders, Inborn
Conditions
Keywords
Argininosuccinate Lyase Deficiency, Urea Cycle Disorder
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.
Interventions
DIETARY_SUPPLEMENTNeo-ASA
Dietary supplement with nitric oxide in the form of a lozenge called Neo-ASA.
DIETARY_SUPPLEMENTPlacebo
Dietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA
Sponsors
Rare Diseases Clinical Research Network
Neogenis Laboratories
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Randomization for treatment assignment is by the providing Institution's Investigational Pharmacy Services.
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.
Eligibility
Sex/Gender
ALL
Age
6 Years to 50 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delis-Kaplan Executive Function System - Tower subtest | 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 | 24 weeks | Change in the scores from baseline to 24 weeks with drug vs placebo |
| Grip Strength | 24 weeks | Change in the scores from baseline to 24 weeks with drug vs placebo |
| Grooved Pegboard | 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) | 24 weeks | Change in the scores from baseline to 24 weeks with drug vs placebo |
| Tower of London Test | 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 | 24 weeks | Change in the scores from baseline to 24 weeks with drug vs placebo |
Countries
United States
Outcome results
None listed