Arginine and Buphenyl in Patients With Argininosuccinic Aciduria (ASA), a Urea Cycle Disorder
| Status: | Completed |
|---|---|
| Conditions: | Other Indications, Other Indications |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 5 - Any |
| Updated: | 2/2/2018 |
| Start Date: | February 2008 |
| End Date: | November 2012 |
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.
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.
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.
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
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