Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder

Descriptive Information
Brief Title † Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder
Official Title † A Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients With Argininosuccinic Aciduria
Brief Summary Urea cycle disorders are inherited illnesses in which the body does not produce enough of the chemicals that remove ammonia, a byproduct of protein metabolism, from the blood stream. Elevated ammonia levels can lead to brain damage and death. Argininosuccinic aciduria (ASA) is a type of urea cycle disorder that is characterized specifically by high levels of argininosuccinic acid, a chemical involved in the urea cycle. People with ASA are at risk for serious liver damage, which may be due to the elevated levels of argininosuccinic acid. Sodium phenylbutyrate (Buphenyl-TM) is a drug that has been used to treat other types of urea cycle disorders. This study will evaluate whether Buphenyl-TM in conjunction with decreased arginine dose (in addition to a normal regimen of protein) will improve short-term liver function and decrease plasma citrulline and ASA levels in people with ASA.
Detailed Description The cause of liver damage in people with ASA is unknown. However, because ASA is the only urea cycle disorder that is characterized by both liver damage and elevated levels of argininosuccinic acid, researchers believe that the elevated acid levels cause the liver damage. Common treatments for urea cycle disorders include a low-protein diet and arginine supplementation, which, when combined, help to decrease ammonia levels in the blood. Buphenyl-TM may aid in lowering ammonia and argininosuccinic acid levels. Although Buphenyl-TM has been FDA-approved for use in people with some types of urea cycle disorders, there is little information on the effectiveness of the drug in children with ASA. This study will evaluate whether treatment of ASA patients with Buphenyl-TM in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production. Initially, participants in this double-blind, placebo-controlled, crossover study will undergo a 3-day washout period during which no Buphenyl-TM will be given. They will then be randomly assigned to one of two groups: either Buphenyl-TM (500 mg/kg/day or 10 grams/m2) and arginine (100 mg/kg/day or 2 grams/m2)), or arginine alone (500 mg/kg/day or 10 grams/m2). Participants will remain on this initial treatment arm for 1 week, at the conclusion of which an assessment of hepatic synthetic function, ureagenesis, and nitric oxide production will be performed. After this assessment, participants will undergo a second 3-day washout and then crossover to the other treatment arm for 1 week. At the end of the 1-week treatment period, a second assessment will be performed. During the washout period before each treatment period, no Buphenyl-TM will be administered, and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/2.
Study Phase Phase 2
Study Type † Interventional
Study Design † Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Primary Outcome Measure † Measures of Liver Function: AST and ALT
Secondary Outcome Measure † Argininosuccinic Acid Levels
Condition † Argininosuccinic Aciduria Amino Acid Metabolism, Inborn Errors Urea Cycle Disorders
Intervention † DrugSodium Phenylbutyrate
Study Arms / Comparison Groups HDA High Dose Arm Wash-out then 7 days of: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA LDA Low Dose Arm Wash-out followed by 7 days of: Arg 100 mg/kg/d or 2 g/m2 BSA NaPBA 500 mg/kg/d or 10 g/m2 BSA
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Drug
Estimated Enrollment † 12
Start Date † February 2008
Completion Date November 2012
Primary Completion Date May 2011
Eligibility Criteria † Inclusion Criteria: - Has confirmed diagnosis of ASA by amino acid or enzyme assay - Has a history of adequate compliance to the diet and treatment - Able to take oral or G-tube medication - Able to perform 24 hour urine collection - Agrees to travel to Baylor College of Medicine - If female, of child bearing potential, and sexually active, agrees to use an acceptable method of birth control - Greater than 5 years of age Exclusion Criteria: - Has a history of congestive heart failure, severe renal insufficiency, or any condition that causes sodium retention or edema - Currently taking Probenecid, Haloperidol, Valproate or oral corticosteroids - Pregnant or lactating - Currently being treated for an acute illness - Has co-morbid associations causing difficulties in the detection of hyperammonemic episodes, liver damage, or difficulties in the diet compliance - Has known hypersensitivity to sodium phenylbutyrate - Has taken any experimental medication within the last 30 days - Has renal insufficiency with creatinine greater than 1.5 mg/dl at screening
Gender Both
Ages 5 Years - N/A
Accepts Healthy Volunteers No
Contacts ††
Location Countries † United States
Administrative Information
NCT ID † NCT00345605
Organization ID RDCRN 5102
Secondary IDs †† U54HD061221
Responsible Party Sponsor-Investigator
Study Sponsor † Brendan Lee
Collaborators †† Office of Rare Diseases (ORD)
Investigators † Principal Investigator: Brendan Lee, MD, PhD, Baylor College of Medicine
Information Provided By
Verification Date October 2015
First Received Date † June 26, 2006
Last Updated Date October 6, 2015
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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