Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD

• Sponsor: Baylor College of Medicine (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03064048
• Collaborator: Rare Diseases Clinical Research Network (Other), Neogenis Laboratories (Other)
• Enrollment: 16
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 75.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Argininosuccinate Lyase Deficiency; Urea Cycle Disorder; Urea Cycle Disorders, Inborn; Argininosuccinic Aciduria	Dietary Supplement: Neo-ASA; Dietary Supplement: Placebo	N/A

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

• Study Type: Interventional
• Anticipated Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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.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 (Participant, Care Provider, Investigator)
• Masking Description: Randomization for treatment assignment is by the providing Institution's Investigational Pharmacy Services.
• Primary Purpose: Treatment
• Official Title: Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)
• Actual Study Start Date: Sep 15, 2017
• Anticipated Primary Completion Date: May 31, 2023
• Anticipated Study Completion Date: Dec 31, 2023

Arms and Interventions

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: Neo-ASA; 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: Placebo; Dietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA

Outcome Measures

Primary Outcome Measures

1. Delis-Kaplan Executive Function System - Tower subtest [24 weeks]

   Change in the scores from baseline to 24 weeks with drug vs placebo

2. 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

3. Grip Strength [24 weeks]

   Change in the scores from baseline to 24 weeks with drug vs placebo

4. Grooved Pegboard [24 weeks]

   Change in the scores from baseline to 24 weeks with drug vs placebo

5. 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

6. Tower of London Test [24 weeks]

   Change in the scores from baseline to 24 weeks with drug vs placebo

7. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Baylor College of Medicine	Houston	Texas	United States	77030

Sponsors and Collaborators

• Baylor College of Medicine
• Rare Diseases Clinical Research Network
• Neogenis Laboratories

Investigators

• Principal Investigator: Sandesh C Nagamani, M.D., Baylor College of Medicine
• Principal Investigator: Brendan Lee, M.D., PhD, Baylor College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK51784/

• Responsible Party: Sandesh Chakravarthy Sreenath Nagamani, Principal Investigator, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT03064048
• Other Study ID Numbers: H-40143
• First Posted: Feb 24, 2017
• Last Update Posted: Aug 9, 2022
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sandesh Chakravarthy Sreenath Nagamani, Principal Investigator, Baylor College of Medicine: Argininosuccinate Lyase Deficiency; Urea Cycle Disorder
• Additional relevant MeSH terms: Urea Cycle Disorders, Inborn; Argininosuccinic Aciduria; Disease

Study Results

No Results Posted as of Aug 9, 2022