A Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine (100 mg/kg/day) Compared to High-Dose Arginine (500 mg/kg/day) Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA)

Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. At present there is little information on the use of sodium phenylbutyrate (Buphenyl™) in children with argininosuccinic aciduria (ASA). It is hoped that this drug may help lower ammonia and argininosuccinic acid levels in patients with ASA. Through this study we hope to learn whether the use of sodium phenylbutyrate (Buphenyl™) in patients with ASA, in addition to diet and arginine therapy, will decrease liver damage and the number of periods during which ammonia levels are high.

The primary study objective is to determine if the treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) 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.

Twelve patients with ASA will be studied using a randomized, cross-over design. Medical records will be reviewed to confirm the diagnosis prior to enrollment. Patients will be on the each arm of the study for one week each preceded by a three day washout period. Patients will come to the Baylor College of Medicine General Clinical Research Center in Texas Children's Hospital for an inpatient hospitalization. This hospitalization is for diet control, clinical evaluation, and stable isotope infusions for measurement of in vivo rates of ureagenesis and nitric oxide production. During the washout periods Buphenyl™ or other alternative route medications, e.g., benzoate, will be discontinued and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/m2.

Following randomization, subjects will be maintained on either high-dose arginine (500 mg/kg/day or 10 grams/m2) alone, or the alternative of low-dose arginine (100 mg/kg/d or 2 grams/m2) along with sodium phenylbutyrate (500 mg/kg/day or 10 grams/m2). For the second week they will be crossed over to the other arm of the study preceded by another three day washout. Previous medications and dietary protein intake (0.6 g/kg/day or current metabolic diet) will be continued during both arms of the study. The two arms may be performed as separate ten-day admissions.

The decision to design the study with two arms, high-dose arginine and low-dose arginine/Buphenyl™, was reached after weighing several considerations. First, the current accepted practice for treatment of ASA is high-dose arginine. Based on metabolic flux studies, we have quantified the effects of this dose of arginine as compared to standard doses of Buphenyl™/phenylacetate on ureagenesis. Since the study is not designed or intended to address the independent effects of Buphenyl™ as compared to arginine alone, Buphenyl™ was added for safety reasons to accommodate loss of clearance of nitrogen by decreasing the arginine dose.

Moreover, based on our experience with recruiting for previous versions of this study, most ASA patients with liver dysfunction are on an alternative route ammonia scavenger medication in addition to arginine. We found that this has in fact become an accepted practice.

Hence, when considering study design from both a safety and recruitment perspective, it was most reasonable to design the study to investigate specifically the hypothesis that the production and presence of argininosuccinic acid leads to liver dysfunction. Since both low-dose arginine with Buphenyl™ and high-dose arginine alone lead to a decreased production of argininosuccinic acid, and both are currently accepted therapies in ASA and UCDs in general, the need to address their effects distinctly is not being investigated at this time.

Sodium phenylbutyrate dosage will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients. Daily dosage will be given in equally divided doses 4 times per day. In order to ensure that the study remains double-blind to investigators, study staff and subjects, the Investigational Pharmacy Service at Texas Children's Hospital will dispense both the Buphenyl™ and arginine in powder form which is compounded into capsules or will be mixed with syrpalta (up to 5 grams will dissolve in 10cc liquid) and administered orally or through nasogastric or gastrostomy tube. No nasogastric tube should be placed or gastrostomy performed solely for the purpose of inclusion in this study. Because the reported adverse effects of sodium phenylbutyrate include gastritis, participants will be started on a standard dose of ranitidine (Zantac™), or comparable drug, during both arms of the study.

• Study Design:
  • Interventional
• Study Type:
  • Interventional
  • Randomized
• Total number of consented subjects: 12
• Subject Sample Telemetry Report (SSTR)

Inclusion Criteria

1. If female, of child bearing potential, and sexually active, agrees to use an acceptable method of birth control.
2. Age greater than 5 years*.
3. Has confirmed diagnosis of ASA by amino acid or enzyme assay.
4. Has a history of adequate compliance to the diet and treatment.
5. Able to take oral or G-tube medication.
6. Able to perform 24 hour urine collection.
7. Agrees to travel to Baylor College of Medicine.

*In the 03Mar2010 version of the protocol inclusion criteria, age greater than 5 years was replaced with weight greater than 10 kilograms.

Exclusion Criteria

1. Has a history of congestive heart failure, severe renal insufficiency, or any condition that causes sodium retention or edema
2. Currently taking Probenecid, Haloperidol, Valproate or oral Corticosteroids.
3. Is pregnant or lactating.
4. Is currently being treated for an acute illness
5. Has co-morbid associations causing difficulties in the detection of hyperammonemic episodes, liver damage or difficulties in the diet compliance
6. Has known hypersensitivity to sodium phenylbutyrate
7. Has taken any experimental medication within the last 30 days
8. Has renal insufficiency with creatinine > 1.5 mg/dl at screening

• Study Activated February 24, 2006
• First Accrual April 23, 2008
• Study Closed to accrual November 23, 2010
• Study Final Closed July 25, 2011

• Primary Phenotype: Urea Cycle Disorders, Inborn

• BioProject
• PubMed
• MeSH
• PMC
• Clinical Trials
  • NCT00345605

• Study Chairs
  • Brendan Lee, MD, PhD. Baylor College of Medicine, Houston, TX, USA.
• Principal Investigators
  • Brendan Lee, MD, PhD. Baylor College of Medicine, Houston, TX, USA.
  • Jeffrey Krischer, PhD. Data Management and Coordinating Center, University of South Florida, Tampa, FL, USA.
• Funding Source
  • U54-HD061221-06. National Institutes of Health, Bethesda, MD, USA.