Clinical trial NCT02252770: Nitric Oxide Supplementation in Argininosuccinic Aciduria
Official title: Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinic Aciduria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Argininosuccinic Aciduria
Argininosuccinate Lyase Deficiency
Urea Cycle Disorders
Keywords: ASA
ASLD
UCD
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
First posted: 2014-09-30
Enrollment: 12
Sex: ALL
Minimum age (years): 8
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Vascular endothelial function as assessed by FMD of brachial artery
timeFrame: 2 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Sandesh CS Nagamani, MD, FACMG
role: PRINCIPAL_INVESTIGATOR
References:
citation: Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R; International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257-65. doi: 10.1016/s0735-1097(01)01746-6.
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 SC, Lee B, Erez A. Optimizing therapy for argininosuccinic aciduria. Mol Genet Metab. 2012 Sep;107(1-2):10-4. doi: 10.1016/j.ymgme.2012.07.009. Epub 2012 Jul 20.