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.

Study Overview

• Status: Completed
• Conditions: Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders; Argininosuccinic Aciduria
• Intervention / Treatment: Drug: Sodium Phenylbutyrate; Drug: Arginine

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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 Names: 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: 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	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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measures of Liver Function: AST and ALT	Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured.	Measured after each 1-week treatment period
Measures of Liver Function: PT and PTT	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.	Measured after each 1-week treatment period
Measures of Liver Function: Coagulation Factors	Plasma levels of coagulation factors I and IX were used as measures of hepatic synthetic function since the treatment duration was short.	Measured after each 1-week treatment period
Measures of Liver Function: INR	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.	Measured after each 1-week treatment period

Secondary Outcome Measures

Outcome Measure	Time Frame
Argininosuccinic Acid Levels	Measured after each 1-week treatment period
Arginine Levels	Measured after each 1-week treatment period
Urea Production Rate	Measured after each 1-week treatment period

Collaborators and Investigators

• Sponsor: Brendan Lee
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Rare Diseases Clinical Research Network; Office of Rare Diseases (ORD)
• Investigators: Principal Investigator: Brendan Lee, MD, PhD, Baylor College of Medicine

Publications and helpful links

General Publications

• Annet L, Materne R, Danse E, Jamart J, Horsmans Y, Van Beers BE. Hepatic flow parameters measured with MR imaging and Doppler US: correlations with degree of cirrhosis and portal hypertension. Radiology. 2003 Nov;229(2):409-14. doi: 10.1148/radiol.2292021128. Epub 2003 Sep 11.
• Lu LG, Zeng MD, Wan MB, Li CZ, Mao YM, Li JQ, Qiu DK, Cao AP, Ye J, Cai X, Chen CW, Wang JY, Wu SM, Zhu JS, Zhou XQ. Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters. World J Gastroenterol. 2003 Nov;9(11):2574-8. doi: 10.3748/wjg.v9.i11.2574.
• Scaglia F, Marini J, Rosenberger J, Henry J, Garlick P, Lee B, Reeds P. Differential utilization of systemic and enteral ammonia for urea synthesis in control subjects and ornithine transcarbamylase deficiency carriers. Am J Clin Nutr. 2003 Oct;78(4):749-55. doi: 10.1093/ajcn/78.4.749.
• Lee B, Yu H, Jahoor F, O'Brien W, Beaudet AL, Reeds P. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8021-6. doi: 10.1073/pnas.140082197.
• Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-70. No abstract available.

Study record dates

Study Major Dates

• Study Start: February 1, 2008
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: June 26, 2006
• First Submitted That Met QC Criteria: June 26, 2006
• First Posted (Estimate): June 28, 2006

Study Record Updates

• Last Update Posted (Actual): January 31, 2018
• Last Update Submitted That Met QC Criteria: January 26, 2018
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: ASA; Argininosuccinic Acid Lyase Deficiency
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Amino Acid Metabolism, Inborn Errors; Argininosuccinic Aciduria; Antineoplastic Agents; 4-phenylbutyric acid
• Other Study ID Numbers: RDCRN 5102; U54HD061221 (U.S. NIH Grant/Contract)