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

This study has been completed.
Sponsor:
Collaborators:
Rare Diseases Clinical Research Network
Information provided by (Responsible Party):
Children's Research Institute
ClinicalTrials.gov Identifier:
NCT00345605
First received: June 26, 2006
Last updated: November 3, 2014
Last verified: November 2014

June 26, 2006
November 3, 2014
February 2008
May 2011   (final data collection date for primary outcome measure)
  • Measures of Liver Function: AST and ALT [ Time Frame: Measured after each 1-week treatment period ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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, raised to the power of the ISI value for the analytical system being used.
Rate of progression of liver disease
Complete list of historical versions of study NCT00345605 on ClinicalTrials.gov Archive Site
  • Argininosuccinic Acid Levels [ Time Frame: Measured after each 1-week treatment period ] [ Designated as safety issue: No ]
  • Arginine Levels [ Time Frame: Measured after each 1-week treatment period ] [ Designated as safety issue: No ]
  • Urea Production Rate [ Time Frame: Measured after each 1-week treatment period ] [ Designated as safety issue: No ]
  • Frequency and severity of hyperammonemic crises
  • Argininosuccinic acid levels
  • Citrulline levels
  • Urea production rate
Not Provided
Not Provided
 
Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder
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

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Argininosuccinic Aciduria
  • Amino Acid Metabolism, Inborn Errors
  • Urea Cycle Disorders
  • Drug: Sodium Phenylbutyrate
    None will be administered during the washout period; 500 mg/kg/day or 10 grams/m2 will be administered during the first one week treatment period in addition to arginine
    Other Name: Buphenyl-TM
  • Drug: Arginine
    Standard therapeutic dose of 500 mg/kg/day or 10 grams/2 will be administered during the washout periods, during the first one week treatment period when receiving arginine plus Buphenyl, 100 mg/kg/day or 2 grams/m2 will be administered, during the second treatment week, when receiving arginine alone, 500 mg/kg/day or 10 grams/m2 will be administered
  • Experimental: HDA

    High Dose Arm

    Wash-out then 7 days of:

    Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA

    Interventions:
    • Drug: Sodium Phenylbutyrate
    • Drug: Arginine
  • Experimental: 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

    Interventions:
    • Drug: Sodium Phenylbutyrate
    • Drug: Arginine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
12
November 2012
May 2011   (final data collection date for primary outcome measure)

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
Both
5 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00345605
RDCRN 5102, U54HD061221
Yes
Children's Research Institute
Children's Research Institute
  • Office of Rare Diseases (ORD)
  • Rare Diseases Clinical Research Network
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Brendan Lee, MD, PhD Baylor College of Medicine
Children's Research Institute
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP