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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

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 Summary:

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 s
Sponsor: Brendan Lee

Current Primary Outcome:

  • Measures of Liver Function: AST and ALT [ Time Frame: Measured after each 1-week treatment period ]
    Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured.
  • Measures of Liver Function: PT and PTT [ Time Frame: Measured after each 1-week treatment period ]
    Prothrombin time (PT) and partial thromboplastin time (PTT) were measured PT measures factors I (fibrinogen), II (prothrombin), V, VII, and X, while PTT is a performance indicator of the efficacy of the common coagulation pathways.
  • Measures of Liver Function: Coagulation Factors [ Time Frame: Measured after each 1-week treatment period ]
    Plasma levels of coagulation factors I and IX were used as measures of hepatic synthetic function since the treatment duration was short.
  • Measures of Liver Function: INR [ Time Frame: Measured after each 1-week treatment period ]
    The result (in seconds) for a prothrombin time performed on a normal individual will vary according to the type of analytical system employed. This is due to the variations between different batches of manufacturer's tissue factor used in the reagent to perform the test. The INR was devised to standardize the results. Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an international reference tissue factor. The ISI is usually between 1.0 and 2.0. The INR is the ratio of a patient's prothrombin time to a normal (control) sample,

    Original Primary Outcome: Rate of progression of liver disease

    Current Secondary Outcome:

    • Argininosuccinic Acid Levels [ Time Frame: Measured after each 1-week treatment period ]
    • Arginine Levels [ Time Frame: Measured after each 1-week treatment period ]
    • Urea Production Rate [ Time Frame: Measured after each 1-week treatment period ]


    Original Secondary Outcome:

    • Frequency and severity of hyperammonemic crises
    • Argininosuccinic Acid Levels
    • Citrulline levels
    • Urea Production Rate


    Information By: Baylor College of Medicine

    Dates:
    Date Received: June 26, 2006
    Date Started: February 2008
    Date Completion:
    Last Updated: October 6, 2015
    Last Verified: October 2015