Nitric Oxide Supplementation in Argininosuccinic Aciduria

Study Overview
=================
Brief Summary
-----------------
This is a study involving a dietary supplement. Patients with argininosuccinic aciduria will be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 2 weeks, and then crossed-over to receive the other treatment for two weeks. The investigators expect to see that : 1) Patients with ASA will have a decreased ability for their arteries to dilate due to nitric oxide deficiency, 2) Treatment of ASA with the nitric oxide supplement will improve the ability of their arteries to dilate, and 3) Through the testing of subjects' fibroblasts (cells in connective tissue that produce collagen and other fibers), the investigators hope to predict which patients may respond NO supplementation.

Detailed Description
-----------------
The investigators will perform a double blind, randomized, placebo-controlled, crossover study of NO supplementation in ASA patients assessing endothelial function and blood pressure as primary endpoints, and markers of nitric oxide production as exploratory endpoints. Subjects will receive a nitrite-restricted diet prior to the start and during the trial period. The dietary protein prescriptions will not be altered. After screening, informed consent, subjects will undergo study procedures at the Clinical Research Center (CRC) at Texas Children's Hospital, Houston, TX. Safety laboratories will be performed. Fibroblast and lymphoblast cultures will be established for subsequent studies.A baseline assessment of the vascular endothelial NO production and function will be assessed using FMD of brachial artery using standard techniques (1). Subjects will be randomized to receive either dietary nitric oxide supplement or placebo for 2 weeks, and then crossed-over to receive the other treatment for two weeks. The Investigational Pharmacy Services at Texas Children's Hospital will assign the initial treatment group randomly in a 1:1 ratio using established randomization procedures. Following randomization, subjects will be receive either Neo40® 40 mg/kg/day in two divided doses) or placebo for 14 days. This dose is the dietary supplemental dose and was well-tolerated in the investigators proof of concept treatment subject as well as other clinical studies in cardiovascular disease. Subjects will return on day 14 to the CRC where they will undergo assessment of FMD of the brachial artery, repeated BP measurements, and assay of NO status. The subjects will then be crossed over to receive the alternative treatment and the study procedures will be repeated in identical fashion to the initial arm.

Official Title
-----------------
Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinic Aciduria

Conditions
-----------------
Argininosuccinic Aciduria, Argininosuccinate Lyase Deficiency, Urea Cycle Disorders

Intervention / Treatment
-----------------
* Dietary Supplement: Nitric oxide supplement
* Dietary Supplement: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A confirmed diagnosis of ASA based on biochemical, enzymatic, or genetic testing Capable of completing study procedures History of compliance with diet and treatment Exclusion Criteria: An active infection (viral or bacterial), any condition(s) that may precipitate a metabolic decompensation A hypersensitivity to nitrite A serum creatinine > 1.5 times above the normal A clinical or laboratory abnormality of Grade 3 or greater according to the CTCAE V4.0 (except elevations of AST or ALT which are a part of the disease) which in the view of the Investigator compromises safety

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nitric oxide supplement arm<br>During this arm, subjects will receive a lozenge with nitric oxide supplement | Dietary Supplement: Nitric oxide supplement<br>* Each active comparator supplement is an all natural nitric oxide supplement. Subjects will take one lozenge twice a day.<br>|
| Placebo Comparator: Placebo Arm<br>During this arm, subjects will receive placebo | Dietary Supplement: Placebo<br>* Placebo will not contain nitric oxide supplement.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vascular endothelial function as assessed by FMD of brachial artery | The primary outcome measures will be vascular endothelial function as assessed by the flow mediated dilatation (FMD) of the brachial artery measured by Doppler ultrasound. | 2 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ASA, ASLD, UCD