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
| Registry | NCT00345605 |
|---|---|
| Status | Completed |
| Phase | Phase 2 |
| Study type | Interventional; randomized, crossover, masking: double, treatment |
| Enrollment | 12 (Actual) |
| Sponsor | Brendan Lee (Other); collaborators: Office of Rare Diseases (ORD), Rare Diseases Clinical Research Network, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| Conditions | Argininosuccinic Aciduria, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders |
| Interventions | Sodium Phenylbutyrate, Arginine (Drug) |
| Dates | start 2008-02-01, primary completion 2011-05-01, completion 2012-11-01, first posted 2006-06-28, last updated 2018-01-31 |
| Locations | 1 site in United States |
Related Papers Related Patents Related Grants Related Experts
All trials for Argininosuccinic Aciduria All trials for Amino Acid Metabolism, Inborn Errors All trials of Sodium Phenylbutyrate All trials of Arginine
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.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| HDA | Experimental | Drug: Sodium Phenylbutyrate; Drug: Arginine | High Dose Arm Wash-out then 7 days of: Arg 500 mg/kg/d or 10 g/m2 BSA Placebo instead of NaPBA |
| LDA | Experimental | Drug: Sodium Phenylbutyrate; Drug: Arginine | 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 |
Sex: All, ages: 5 Years to any
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
| Milestone | High Dose First | Low Dose First |
|---|---|---|
| Started | 6 | 6 |
| Completed | 6 | 6 |
| Not completed | 0 | 0 |
Time frame: during both of the 7 day treatment phases
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|---|---|---|
| High-dose Arginine Alone | 0 | 0/12 (0.0%) | 1/12 (8.3%) |
| Low-dose Arginine Plus Buphenyl | 0 | 0/12 (0.0%) | 1/12 (8.3%) |
| Term | Organ system | High-dose Arginine Alone | Low-dose Arginine Plus Buphenyl |
|---|---|---|---|
| Vomiting | Gastrointestinal disorders | 1/12 | 1/12 |
| Hyperammonemia | Metabolism and nutrition disorders | 1/12 | 1/12 |
| Facility | City | Country | Status |
|---|---|---|---|
| Baylor College of Medicine | Houston, Texas | United States |
NIH grants: U54HD061221