Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD

Not Applicable

Completed

• Conditions: Argininosuccinic Aciduria; Argininosuccinate Lyase Deficiency; Urea Cycle Disorder; Urea Cycle Disorders, Inborn
• Interventions: Dietary Supplement: Neo-ASA; Dietary Supplement: Placebo

• Registration Number: NCT03064048
• Lead Sponsor: Baylor College of Medicine

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.

Study Timeline

• Study First Submitted: 2017-02-10
• Study First Submitted QC: 2017-02-21
• Study First Posted: 2017-02-24
• Study Start: 2017-09-15
• Primary Completion: 2023-01-31
• Study Completion: 2023-01-31
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-24
• Last Update Posted: 2023-02-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Neo-ASA	Neo-ASA	During this arm the participant will receive a lozenge with nitric oxide as a dietary supplement twice daily.
Placebo	Placebo	During this arm the participant will receive a lozenge which will not contain nitric oxide as a dietary supplement twice daily.

Primary Outcome Measures

Name	Time	Method
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
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
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
Grooved Pegboard	24 weeks	Change in the scores from baseline to 24 weeks with drug vs placebo
Delis-Kaplan Executive Function System - Tower subtest	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

Trial Locations

Locations (1)

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States